Clinical trial NCT01633112
Conditions: Relapsing-remitting Multiple Sclerosis (RRMS)
Sponsor: Novartis Pharmaceuticals
Start date: 2012-08-09; Completion date: 2018-04-30
Enrollment: 1064 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to demonstrate that at least one dose (0.5 mg followed by 0.25 mg) of fingolimod is superior to glatiramer acetate 20 mg SC in reducing the ARR up to 12 months in patients with relapsing-remitting MS

Detailed description:
This was a multicenter, randomized, rater- and dose-blinded, study to compare the efficacy and safety of 0.25 mg and 0.5 mg of fingolimod with glatimer acetate 20 mg s.c. in patients with RRMS.

This study consisted of 3 periods:

* Screening Period: up to 45 days for all patients
* Treatment Period: 12 months of glatiramer acetate 20 mg, fingolimod 0.25 mg, or fingolimod 0.5 mg
* Follow-up occurred 3 months (12 weeks) after the last dose of study drug for all patients The informed consent form was signed prior to any study related activities at the screening visit. Randomization to either treatment group was preformed at visit 1 after a diligent check of applicable in- and exclusion criteria in a 1:1:1 ratio (changed to 5:3:2 after implementation of Amendment 2 in 2015).

Treatment groups:

* fingolimod 0.5 mg/day orally for up to 12 months
* fingolimod 0.25 mg/day orally for up to 12 months
* glatiramer acetate 20 mg/day subcutaneously for up to 12 months

Arms: arm 1: orally once daily arm 2: orally once daily arm 3: subcutaneous once daily
Interventions: intervention 1: fingolimod intervention 2: glatiramer acetate
Intervention descriptions: intervention 1: capsule intervention 2: subcutaneous injection

Protocol documents:
Prot_000.pdf: 
Clinical Development
FTY720/Fingolimod
Clinical Trial Protocol CFTY720D2312 / NCT01633112
A 12-month, randomized, rater- and dose-blinded study to 
compare the efficacy and safety of fingolimod 0.25 mg 
and 0.5 mg administered orally once daily with glatiramer 
acetate 20 mg administered subcutaneously once daily in 
patients with relapsing-remitting multiple sclerosis
Authors:
 
Document type:
Amended Protocol Version
Version number:
v02 Clean
EUDRACT number:
Not applicable
Development phase:
IIIb
Release date:
20-Jul-2015
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Template version 24 May 2011
 


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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.................................................................................................................9
Protocol synopsis...............................................................................................................23
1
Introduction .......................................................................................................................28
1.1
Background............................................................................................................28
1.2
Purpose ..................................................................................................................31
2
Study objectives.................................................................................................................32
2.1
Primary objective...................................................................................................32
2.2
Secondary objectives .............................................................................................32
32
33
3
Investigational plan ...........................................................................................................33
3.1
Study design...........................................................................................................33
3.2
Rationale of study design.......................................................................................35
3.3
Rationale of dose/regimen, duration of treatment .................................................36
3.4
Rationale for choice of comparator .......................................................................36
3.5
Purpose and timing of interim analyses/design adaptations..................................36
4
Population..........................................................................................................................36
4.1
Inclusion criteria ....................................................................................................37
4.2
Exclusion criteria...................................................................................................37
5
Treatment...........................................................................................................................41
5.1
Investigational and control treatment ....................................................................41
5.2
Treatment arms......................................................................................................41
5.3
Treatment assignment............................................................................................41
5.4
Treatment blinding.................................................................................................42
5.5
Treating the patient................................................................................................42
5.5.1
Patient numbering .................................................................................42
5.5.2
Dispensing the study treatment.............................................................43
5.5.3
Supply, storage, and tracking of study treatment..................................43
5.5.4
Instructions for prescribing and taking study treatment........................43
5.5.5
Guidelines for monitoring patients taking their first dose of 
fingolimod.............................................................................................44
 


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5.5.6
Permitted dose adjustments and interruptions of study treatment ........46
5.5.7
Recommendations on treatment of multiple sclerosis relapse..............47
5.5.8
Concomitant treatment..........................................................................48
5.5.9
Prohibited treatment..............................................................................48
5.5.10
Discontinuation of study treatment and premature patient 
withdrawal.............................................................................................49
5.5.11
Emergency unblinding of treatment assignment for patients on 
fingolimod.............................................................................................49
5.5.12
Study completion and post-study treatment..........................................50
5.5.13
Early study termination.........................................................................50
6
Visit schedule and assessments .........................................................................................50
6.1
Information to be collected on screening failures..................................................53
6.2
Patient demographics/other baseline characteristics .............................................53
6.3
Treatment exposure and compliance .....................................................................54
6.4
Efficacy..................................................................................................................54
6.4.1
Multiple sclerosis relapse......................................................................54
6.4.2
Expanded Disability Status Scale..........................................................55
6.4.3
Magnetic Resonance Imaging (MRI)....................................................55
56
57
6.4.6
Appropriateness of efficacy assessments..............................................57
6.5
Safety Assessments................................................................................................57
6.5.1
Physical examination ............................................................................57
6.5.2
Vital signs..............................................................................................58
6.5.3
Laboratory evaluations..........................................................................58
6.5.4
Electrocardiogram.................................................................................60
6.5.5
Ophthalmologic examinations and optical coherence tomography ......61
6.5.6
Pregnancy and assessments of fertility .................................................61
61
6.5.8
Chest x-ray ............................................................................................63
6.5.9
Pulmonary function tests.......................................................................63
6.5.10
Dermatological examination.................................................................64
6.5.11
Columbia-Suicide Severity Rating Scale..............................................64
6.5.12
Appropriateness of safety measurements..............................................65
6.6
Other assessments..................................................................................................65
6.6.1
Health-related quality of life.................................................................65
6.6.2
Resource utilization...............................................................................66
 


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6.6.3
Pharmacogenetics/pharmacogenomics .................................................66
66
7
Safety monitoring..............................................................................................................67
7.1
Adverse events.......................................................................................................67
7.2
Serious adverse event reporting.............................................................................68
7.2.1
Serious adverse event notification: multiple sclerosis relapse..............69
7.3
Pregnancies............................................................................................................69
7.4
Data safety monitoring board ................................................................................69
8
Data review and database management.............................................................................70
8.1
Site monitoring ......................................................................................................70
8.2
Data collection.......................................................................................................70
8.3
Database management and quality control............................................................70
9
Data analysis......................................................................................................................71
9.1
Analysis sets ..........................................................................................................71
9.2
Patient demographics and other baseline characteristics.......................................72
9.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................72
9.4
Analysis of the primary variable............................................................................72
9.4.1
Variable.................................................................................................72
9.4.2
Statistical model, hypothesis, and method of analysis..........................72
9.4.3
Handling of missing values, censoring, and discontinuations ..............74
9.5
Analysis of secondary variables ............................................................................75
9.5.1
Efficacy variables..................................................................................75
9.5.2
Safety variables .....................................................................................77
9.5.3
Resource utilization...............................................................................78
9.5.4
Health related quality of life .................................................................78
79
9.5.6
Pharmacogenetics/pharmacogenomics .................................................79
9.5.7
Biomarkers............................................................................................79
9.5.8
Pharmacokinetic/pharmacodynamic .....................................................79
9.6
Sample size calculation..........................................................................................79
9.7
Power for the key secondary hypotheses...............................................................80
80
9.9
Interim analysis......................................................................................................80
10 Ethical considerations........................................................................................................81
10.1
Regulatory and ethical compliance........................................................................81
10.2
Informed consent procedures.................................................................................81
 


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10.3
Responsibilities of the investigator and IRB/IEC..................................................81
10.4
Publication of study protocol and results...............................................................81
11 Protocol adherence ............................................................................................................82
11.1
Protocol amendments.............................................................................................82
12 References (Available Upon Request) ..............................................................................82
13 Appendices ........................................................................................................................85
Appendix 1: Clinically notable laboratory values and vital signs.....................................85
Appendix 2:  2010 Revisions to the McDonald diagnosis criteria for MS .......................87
Appendix 3:  Guidance on safety monitoring....................................................................89
Appendix 4:  Guidance for ophthalmic monitoring ..........................................................94
96
List of tables
Table 6-1
Assessment schedule.............................................................................51
Table 6-2
Abbreviated schedule of assessments for patients who discontinue 
study drug..............................................................................................52
55
List of figures
Figure 3-1
Study design..........................................................................................34
 


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List of abbreviations
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AP
alkaline phosphatase
ARR
annualized relapse rate
AST
aspartate aminotransferase
AV
atrioventricular
CFR
United States Code of Federal Regulations
CNS
central nervous system
CO
carbon monoxide
CHMP
Committee for Medicinal Products for Human Use
CPO
Country Pharma Organization
CRF
case report forms
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DLCO
diffusion capacity of carbon monoxide
DMD
disease modifying drug
DS&E
Drug Safety and Epidemiology
DSMB
data safety monitoring board
DTPA
diethylenetriamine penta-acetic acid
eCRF
electronic case report/record form
ECG
electrocardiogram
EDSS
Expanded Disability Status Scale
EOT
end of treatment
FA
fluorescein angiography
FACS
fluorescein activated cell sorter
FAS
full analysis set
FEV1
forced expiratory volume in 1 second
FS
functional system
FVC
forced vital capacity
Gd
gadolinium
 


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GGT
gamma glutamyl-transferase
HbA1c
glycosylated hemoglobin/hemoglobin A1c
HRCT
high-resolution computed tomography
HSV
herpes simplex virus
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
independent ethics committee
IFN
interferon
Ig
immunoglobulin
IgG
immunoglobulin G
IM
intramuscular
IRB
institutional review board
IV
intravenous
IVRS
interactive voice response system 
MedDRA
Medical Dictionary for Regulatory Activities
MS
multiple sclerosis
MRI
magnetic resonance imaging
OCT
optical coherence tomography
QoL
quality of life
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
pharmacodynamic
PFT
pulmonary function test
PRO
patient reported outcome
RRMS
relapsing-remitting multiple sclerosis
 


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SD
standard deviation
S1P
sphingosine 1-phosphate
SAE
serious adverse event
SC
subcutaneous
Treg
regulatory T cell
TSQM
Treatment Satisfaction Questionnaire for Medication
ULN
upper limit of normal
VZV
varicella zoster virus
WBC
white blood cells
 


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Baseline
The collection of pre-randomization information on subsequently 
randomized patients for future description and analysis. For any data 
analysis, the baseline for any data point will be clearly identified in the 
Statistical Analysis Plan.
Control drug
A study drug used as a comparator to reduce assessment bias, assess 
internal study validity, and/or evaluate comparative effects of the 
investigational drug
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e., before starting any of the procedures 
described in the protocol)
Investigational drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.”
Medication number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IVR system
Patient number
A number assigned to each patient who enrolls in the study. When 
combined with the center number, a unique identifier is created for each 
patient in the study.
Period
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc.
Premature patient withdrawal
Point/time when the patient exits from the study before the planned 
completion of all study drug administration and assessments; at this time 
all study drug administration is discontinued and no further assessments 
are planned
Randomization number
A unique identifier assigned to each randomly assigned patient, 
corresponding to a specific treatment arm assignment
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when 
study drug was discontinued whichever is later
Study drug
Any drug administered to the patient as part of the required study 
procedures; includes investigational drug and any control drugs
Study drug discontinuation
Point/time when patient permanently stops taking study drug for any 
reason; may or may not also be the point/time of premature patient 
withdrawal
Variable
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints
 


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Amendment 02
Amendment rationale
This amendment implements changes to the CFTY720D2312 protocol amendment 1 (dated 
20-Nov-2012) to address recommendations and requests received from the United States (US) 
Food and Drug Administration (FDA). 
The FDA has approved the Sponsor’s proposal to reduce the sample size for this study. The 
FDA recommended to keep the number of patients in the fingolimod (FTY720) 0.25-mg 
treatment arm the same and agreed to reduce the other two treatment arms by up to 50% of the 
original sample size. This has led to a change in the randomization ratio between the three 
treatment groups and as a consequence an alteration of the calculated sample size. This 
sample size provides approximately 90% power for the primary objective. After the 
introduction of protocol amendment 2, the anticipated total number of patients to be screened 
is reduced to approximately 2610 from original 3190 patients. A screening failure rate of 25% 
is anticipated (supported by the current trend in this D2312 study [status Feb 2015]) and a 
total of 1960 randomized patients are targeted: fingolimod 0.25 mg (total 847 patients), 
fingolimod 0.5 mg (total 615 patients), and glatiramer acetate 20 mg (total 498 patients),
respectively.
In addition, this amendment implements modifications to the inclusion/exclusion criteria. 
These modifications are prompted by:

Feedback from study investigators and consultation with the study advisory group to help 
widening the pool of eligible subjects

Alignment of the protocol with fingolimod’s current US prescribing information and the 
prescribing information in other countries which are within the scope of this study as this 
is a Phase IIIb study with a marketed drug  
The exclusion criterion 1 related to history of malignancy was rationalized to allow inclusion 
of patients who are now free of the past malignancy and have no trace of malignancy for the 
last 5 years.
The exclusion criterion 3 related to use of previous multiple sclerosis (MS) treatments was 
modified bearing in mind the likely duration of pharmacodynamic (PD) action of previous 
therapies and the assessments inherent in the screening assessments (e.g., complete blood 
counts) to rule out the persistence of such PD actions. Also, the criterion was modified to 
introduce guidance on the washout for newly approved disease-modifying therapies namely 
teriflunomide and dimethyl fumarate.
The requirement for serology testing of hepatitis A, B, C, and E, at Screening was omitted. 
This criterion (exclusion criterion 8 in protocol amendment version 1) has been modified to be 
in alignment with the current US prescribing information and the prescribing information in 
other countries which are within the scope of this study which does not require such screening 
before initiating treatment with fingolimod in clinical practice. The liver functions are being 
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instances of liver infections/impairment (if any) early and are considered as adequate 
safeguards. 
The current exclusion criterion 8 regarding mandatory serologic screening for antibodies 
against varicella zoster virus (VZV) is a modification which also allows for alternative
acceptable evidence of immunity (as per Center for Disease Control guidance). This brings 
the protocol in alignment with the guidance in the current US prescribing information in this 
context. 
The current exclusion criteria 12, 13, and 14 have modified text to align with the 
US prescribing information and the prescribing information in other countries which are 
within the scope of this study. The exclusion clauses in protocol amendment version 1 were 
more restrictive than that recommended in the US prescribing information resulting in 
exclusion of those patients with certain pre-existing cardiac conditions or on concomitant 
drugs prolonging heart rate or atrioventricular (AV) conduction, who would have been 
otherwise eligible to initiate fingolimod with extended monitoring.
Certain clarifications and corrections were also done in the protocol as follows:
The exclusion criterion 16 provides clarification that patients with controlled asthma are 
allowed to participate in the study.
The prohibition period for the administration of a live or live-attenuated vaccine after 
fingolimod discontinuation was corrected from 12 to 8 weeks (as per US prescribing 
information). 
Clarification was provided that the patients known to be allergic to gadolinium (Gd) may 
participate in the trial with magnetic resonance imaging (MRI) performance modified only to 
forgo contrasted MRI images. 
The following erroneous paragraph was deleted: Patients experiencing bradycardia that has 
not resolved by the end of the 6-hour monitoring period must be hospitalized overnight. For 
these patients, the Day 2 dose of fingolimod should be given under the supervision of the 
treating physician, and the 6-hour monitoring period should be repeated per the procedures 
outlined for the first dose. 
Throughout the protocol, clarifications of wording and correction of minor inconsistencies 
were provided for improved study conduct. This included allowance of use of topical and 
inhaled steroids for indications other than MS in Section 5.5.8, relaxation on the dosing 
adjustments of symptomatic therapies for optimal patient care in Section 5.5.8, details of the 
assessments to be performed for ophthalmologic examination in Table 6-1 and Table 6-2, 
 
 
 
.
In Appendix 3, investigators were guided to consider appropriate antihypertensive 
medication/dosage adjustment for newly diagnosed hypertension as well as an aggravation of 
a pre-existing condition. The earlier guidance to consider the discontinuation of study drug 
was deleted as it was an erroneous statement and not in line with the US prescribing 
information of fingolimod. Similarly, clarity was provided on the repeat testing in cases of 
 


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alanine aminotransferase/aspartate aminotransferase rise above 5 times the upper limit of 
normal (ULN). 
Also, further clarity is being provided to investigators for interruption of glatiramer acetate 
when the lymphocyte count decreases below 50% of the baseline levels.
The protocol is also being amended to address safety updates in the investigator brochure 
(Edition 18) – in particular to provide additional guidance for safety monitoring for 
opportunistic infections and for basal cell carcinoma.

Notably, there have been reports of isolated cases of cryptococcal meningitis in MS
patients with relapsing MS receiving fingolimod. As a result, the fingolimod local product 
labeling will be updated to guide prescribers for vigilance, early detection, and diagnosis 
of such cases, should they occur. Similarly, the infection safety monitoring guidance is 
being updated in this protocol (Appendix 3).

Basal cell carcinoma has been reported in patients receiving fingolimod. The physical 
examination section has been amended to ask patients about any new or worsening skin 
lesions and to instruct investigators to refer patients to the dermatologist in cases where 
suspected precancerous or cancerous skin lesions are identified.
The requirement for chest x-ray at Screening was removed as it was considered unnecessary 
by investigators, in line with the current safety profile of fingolimod. The pulmonary function 
testing and clinical examination of the respiratory system are considered to be adequate 
screening measures to evaluate pulmonary status.
Changes to the protocol

The planned number of enrolled patients was reduced from 2250 to 1959 to provide a 
power of approximately 90% for the comparison of the annualized relapse rate (ARR) 
between fingolimod 0.5 mg to glatiramer acetate at a 2-sided significance level of 0.05. 
The power of the statistical test for the comparison of fingolimod 0.25 mg with glatiramer 
acetate will depend on whether the efficacy seen with fingolimod 0.5 mg is maintained in 
the lower dose (the 0.25-mg dose of fingolimod that has never been studied before). 
(Section 3.1, Section 4, and Section 9.6)

The randomization ratio to the three treatment arms (fingolimod 0.25 mg, fingolimod 
0.5 mg, and glatiramer acetate 20 mg) was changed from 1:1:1 to 5:3:2 to comply with the 
FDA recommendations on revision of the sample size in the three arms. The revised 
sample size calculation assumes that this switch will occur when a total of approximately 
700 patients have been randomized to treatment under the original randomization ratio. 
(Section 3.1 and Section 4) 

The alpha-propagation procedure was replaced in protocol amendment 2 by a step-down 
hierarchical testing procedure in which the approved dose of fingolimod is initially tested 
against glatiramer acetate (at a 2-sided significance level of 0.05), and only if this initial 
test is significant will the low dose of fingolimod be tested against glatiramer acetate (also 
 


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at 2-sided significance level of 0.05). This change was introduced because of the alteration 
in the planned number of patients. (Section 9.4.2 and Section 9.6)

Consequently, the original primary objective of the study “The primary objective is to 
demonstrate that at least 1 dose (0.5 mg or 0.25 mg) of fingolimod is superior to 
glatiramer acetate 20 mg subcutaneous (SC) in reducing the annualized relapse rate (ARR)
up to 12 months in patients with relapsing-remitting MS” was reworded to: “The primary 
objective is to demonstrate that at least 1 dose (tested hierarchically 0.5 mg followed by 
0.25 mg) of fingolimod is superior to glatiramer acetate 20 mg SC in reducing the ARR up 
to 12 months in patients with relapsing-remitting MS.” (Section 2.1)

 
 

 
 

Inclusion criterion 7 was removed and appropriate text was added to exclusion criterion 3 
(see the following bullet point) with addition of instruction for dimethyl fumarate. 
(Section 4.1 and Section 5.5.8)

Exclusion criterion 1 was changed as follows: Patients with a history of malignancy of any 
organ system (other than cutaneous basal cell carcinoma) in the last 5 years that do not 
have confirmation of absence of a malignancy prior to randomization. (Section 4.2)

Exclusion criterion 3 was amended. The modified exclusion criterion is as follows:
(Section 4.2)

Intravenous (IV) immunoglobulin (Ig) within 4 weeks before randomization

Immunosuppressive/chemotherapeutic medications (e.g., azathioprine, 
cyclophosphamide, methotrexate) within 6 months before randomization

Natalizumab within 2 months before randomization

Previous treatment with lymphocyte-depleting therapies (e.g., rituximab, alemtuzumab, 
ofatumumab, ocrelizumab, or cladribine) within 1 year before randomization

Previous treatment with mitoxantrone 6 months before randomization

Use of teriflunomide within 3.5 months prior to randomization, except if active 
washout (with either cholestyramine or activated charcoal) was done. In that case,
plasma levels are required to be measured and to be below 0.02 mg/L before 
randomization.
No washout period is necessary for patients treated with dimethyl fumarate, 
interferon (IFN) beta, or glatiramer acetate. Patients being treated with dimethyl 
fumarate, glatiramer acetate, or IFN beta at the screening visit can continue drug 
intake up to the day before Day 1 of this study (i.e., there is no need for a washout 
period).

The earlier (in protocol amendment version 1) exclusion criteria 8 (screening for hepatitis 
A, B, C, and E) was removed. (Section 6.5.3.2 and Table 6-1)
 


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
Current exclusion criterion 8 has the following modified text regarding VZV: Patients 
without acceptable evidence of immunity to VZV at randomization (See Appendix 3 for 
guidance on acceptable evidence of immunity and requirement for serologic testing).
(Section 4.2, Section 6.5.3.2, and Table 6-1)

Exclusion criterion 13 in protocol amendment version 1 has been modified and divided in 
exclusion criteria 12, 13, 14, and 15 (Section 4.2) as listed in the following 4 bullet points:

Exclusion criterion 12: Patients who in the last 6 months experienced any of the 
following cardiovascular conditions or findings in the screening electrocardiogram 
(ECG):
-
myocardial infarction 
-
unstable angina
-
stroke
-
transient ischemic attack
-
decompensated heart failure requiring hospitalization or Class III/IV heart failure

Exclusion criterion 13: Patients with history or presence of a Mobitz Type II AV block, 
or a third-degree AV block or sick sinus syndrome, unless patient has a functioning 
pacemaker 

Exclusion criterion 14: Patients with baseline QTc interval >500 msec 

Exclusion criterion 15: Patients receiving Class Ia (e.g., ajmaline, disopyramide, 
procainamide, quinidine) or Class III antiarrhythmic drugs (e.g., amiodarone, 
bretylium, sotalol, ibutilide, azimilide, dofetilide)

Exclusion criterion 15 in protocol amendment version 1 has become exclusion criterion 16 
and is modified as follows: Patients with severe respiratory disease, pulmonary fibrosis, or 
Class III or IV chronic obstructive pulmonary disease, or with clinically significant lung 
pathology on chest x-ray. Patients with controlled asthma are allowed to enter the study. 
(Section 4.2)

Exclusion criterion 14 in protocol amendment version 1 was deleted: Patients receiving 
current treatment with (at treatment initiation) beta blockers, heart-rate slowing 
calcium-channel blockers (e.g., ivadrabine, verapamil, or diltiazem), or other substances 
which may decrease heart rate such as digoxin, anticholinesterase agents, or pilocarpine. 
Advice from a cardiologist should be sought regarding the switch to nonheart rate 
lowering medicinal products. (Section 4.2) 
Similarly, text was deleted from Section 5.5.4 (Instructions for prescribing and taking 
study treatment): Due to a possible additive effect on heart rate reduction it is 
recommended not to initiate treatment with beta blockers, calcium-channel blockers, or 
digoxin within 1 week before randomization. In patients randomized to treatment with 
fingolimod, treatment with beta blockers, calcium-channel blockers, or digoxin should 
also not be initiated within one week after the start of study drug administration.

Exclusion criterion 25 in protocol amendment version 1 has become exclusion criterion 26 
and revised as follows: Patients with a score of 4 or 5 on the Suicidal Ideation item of the 
Columbia-Suicide Severity Rating Scale (C-SSRS) within 2 years of Screening, or any 
“yes” on the Suicidal Behavior item of the C-SSRS at Screening. (Section 4.2)
 


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
Guidance was provided for re-screening of patients. (Section 4)

Additional monitoring guidelines were added for patients with any pre-existing 
cardiovascular conditions and those receiving concurrent therapy with drugs that slow 
heart rate or AV conduction (e.g., beta blockers, heart rate lowering calcium-channel 
blockers such as diltiazem, verapamil, or digoxin). (Section 5.5.5)

The following paragraph was deleted: “Patients experiencing bradycardia that has not 
resolved by the end of the 6-hour monitoring period must be hospitalized overnight.” For 
these patients, the Day 2 dose of fingolimod should be given under the supervision of the 
treating physician, and the 6-hour monitoring period should be repeated per the procedures 
outlined for the first dose. (Section 5.5.5) 

Topical and inhaled steroids were allowed at the discretion of the treating neurologist for 
indications other than MS. (Section 5.5.8)

There was modification to the statement regarding permitted medications for symptomatic 
treatment of MS. The current text reads as follows: Medications for the symptomatic 
treatment of MS such as baclofen, fampridine, methylphenidate, or modafinil are 
acceptable. As far as possible, every effort should be made to keep the dosages stable from 
Screening through end of treatment (EOT). (Section 5.5.8)

The prohibition period for the administration of a live or live-attenuated vaccine after 
fingolimod discontinuation was corrected from 12 to 8 weeks. The statement that the 
vaccines may be administered once the lymphocyte counts are in laboratory normal range 
was deleted. (Section 5.5.9 and Appendix 3)

Clarification is provided on what assessments are to be performed for ophthalmologic 
examination. The current text reads: The ophthalmology examination will include eye 
history, visual acuity, dilated ophthalmoscopy, and any procedures necessary to assess 
macular edema. Optical coherence tomography and fluorescein angiography will be done 
only if needed to confirm macular edema. (Table 6-1 and Table 6-2) 

Guidance was provided about the patients known to be allergic to Gd: The patients known 
to be allergic to Gd may participate in the trial with MRI assessment modified to forgo the 
contrasted MRI images. (Section 6.4.3)

 

 

Guidance was provided when an MS relapse should be reported as a serious adverse event
(SAE). The text reads: Any MS relapse, as a general rule, should be reported on the 
relapse CRF instead of the adverse event (AE)/SAE forms. However, if, in the judgment 
of the investigator, an MS relapse is unusually severe or unexpected and warrants specific 
notification, then an SAE form must be completed and submitted according to SAE 
reporting procedures outlined above. (Section 7.2.1)
 


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
Guidance on safety monitoring was revised with respect to the actions to be taken with 
newly diagnosed hypertension. The current text is: Newly diagnosed hypertension as well 
as an aggravation of a pre-existing condition must be reported as an AE and appropriate 
antihypertensive medication/dosage adjustment must be considered by the investigator. 
(Appendix 3)

Clarification was provided under guidance on monitoring of patients with elevated liver 
function tests (Appendix 3). The current text is: If alanine aminotransferase/aspartate 
aminotransferase values reach 5 times the ULN, confirmed upon repeat testing within 
2 weeks of the initial result or sooner at the discretion of the investigator, the study drug 
must be permanently discontinued. Patients who develop symptoms suggestive of hepatic 
dysfunction such as unexplained vomiting or jaundice, should have liver enzymes checked 
and fingolimod should be discontinued if significant liver injury is confirmed. 

Investigators were advised to be vigilant for early diagnosis and treatment of cryptococcal 
meningitis and basal cell carcinoma (Appendix 3: Guidance for monitoring of infections; 
Section 6.5.1)

The guidance to investigators for interruption of glatiramer acetate when the lymphocyte 
values decrease below 50% of baseline values was revised. (Appendix 3)

Clarity was provided on the blinded and unblinded reporting of results for fingolimod. 
(Appendix 3)
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs), and health authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the informed consent, sites are 
required to update and submit for approval a revised informed consent that takes into account 
the changes described in this amended protocol.
 


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Amendment 01
Amendment rationale 
This amendment implements changes to the CFTY720D2312 protocol (dated 23-Sep-2011) to 
address recommendations and requests received from the United States Food and Drug 
Administration (FDA) following their review of the protocol and to align aspects of the 
protocol with the current revised fingolimod (Gilenya™) label. 
 
 
 
The main changes involve inclusion of additional safety assessments, to allow comprehensive 
risk/benefit assessment of the 0.5 mg per day fingolimod dose [currently in the market], the 
lower 0.25 mg per day dose [under investigation in this study] and glatiramer acetate [control]. 
The safety assessments that are now being included for all participating patients are regular 
pulmonary function tests, dermatological examinations, ophthalmic examinations and 
assessment of suicidality. Specific guidance is provided for full workup in patients developing 
cardiac symptoms; pulmonary hypertension; ischemic or thrombotic events proteinuria. 
Suicidality assessment is also included in compliance with FDA guidance applicable to all 
drugs that have an effect on the central nervous system. 
Safety sections of this protocol are revised with regard to cardiac safety. In December 2011, 
the company reported a sudden, unexplained death of a patient within 24 hours after the 
administration of the first dose of commercial fingolimod 0.5 mg. While the cause of death is 
unknown, the role of fingolimod cannot be confirmed or excluded. The reporting of this event 
prompted a thorough review the cardiac safety data from clinical trials as well as spontaneous 
reports in the post-marketing setting.
In order to align the protocol with the current revised fingolimod label, this amendment 
additionally updates and modifies (1) specific exclusion criteria, (2) selected safety 
monitoring guidance and (3) revision of the requirements for first dose monitoring following 
fingolimod interruption. 
In addition, the amendment includes changes to facilitate the conduct of the study and 
includes clarifications of wording and other minor corrections.
The study is currently enrolling patients, and approximately 22 patients have been enrolled at 
the time of release of this amendment. 
In summary the changes in the amendment refer to the following:

pulmonary function testing

dermatological examinations

additional ophthalmological examination at 6 months

body weight monitoring

addition of certain laboratory analyses

collection of laboratory analysis data that are not associated with a regular study visit

provision for referral of patient to a specialist in the event of new significant cardiac or 
pulmonary hypertension symptoms
 


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
inclusion of patients with higher glycosylated hemoglobin (HbA1c) levels but without
diabetic neuropathy

collection of additional baseline characteristics for diabetic patients

provision for full diagnostic workup in patients with an ischemic or thrombotic adverse 
event 

a suicide severity rating assessment
Other changes to the protocol either for clarification, to improve conduct of the study, or to 
increase patient safety include:

deletion of exclusion criterion regarding patients with history of vitamin B12 deficiency

clarification of effective contraception methods

deletion of redundant exclusion criterion pertaining to treatment with high dose steroids

additional instructions to minimize risk of unblinding of blinded site personnel

change of day of screening to be as early as 45 days prior to randomization

further specification of study drug storage conditions

 

specification of assay for detecting hepatitis C virus


direction for central laboratory reporting of hematology results to maintain site blinding

 
 

minor wording corrections and administrative changes
The protocol has been amended to expand the population to be evaluated to include diabetic 
patients whose glycosylated hemoglobin levels are moderately elevated. The changes 
included in this amendment will provide additional data for the safety profiles of the study 
treatments.
Changes to the protocol

The authors of the protocol were changed. (Title cover page)

Background (Section 1.1) was revised to include updated patient exposure, updated 
summary of adverse events, addition of atrioventricular (AV) conduction safety 
information, and statement regarding patients with cardiovascular or cerebrovascular 
disease for which fingolimod is not recommended.


 
 
 
 
 
 


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
The screening visit has been changed to occur up to 45 days prior to randomization 
(Section 3.1, Figure 3-1, Table 6-1)

Inclusion criterion #4 was changed to remove reference to systemic steroid use because 
this was covered within exclusion criterion #4. (Section 4.1)

The exclusion criterion regarding the use of intravenous immunoglobulin was changed for 
clarity to exclude any patients receiving intravenous immunoglobulin within 2 months 
prior to randomization. (Section 4.2)

The exclusion criterion regarding uncontrolled diabetes was changed to allow 
participation by diabetics if their HbA1c level is 9% or less and they are without diabetic 
neuropathy. (Section 4.2)

The exclusion criterion regarding history of vitamin B12 deficiency was removed. 
(Section 4.2)

The exclusion criterion regarding serological markers to detect hepatitis C was changed to 
remove anti-hepatitis C virus IgM and to add hepatitis C virus RNA polymerase chain 
reaction (PCR) as an assay. (Section 4.2, Section 6.5.3.2, Table 6-1)

Exclusion criteria were expanded to exclude patients with additional cardiovascular 
conditions and patients receiving treatments which may decrease heart rate. (Section 4.2)

Exclusion criterion #15 was expanded to exclude patients who have clinically significant 
lung pathology by chest x-ray at Screening. A chest x-ray was added to assessments at the 
screening visit if an x-ray within the previous 3 months is not available. (Section 4.2, 
Table 6-1, Section 6.5.8)

Exclusion criterion #22 pertaining to effective contraception was expanded to define 
highly effective methods of contraception. (Section 4.2)

An exclusion criterion was added to exclude patients with a score of “yes” on item 4 or
item 5 of the Suicidal Ideation section of the Columbia-Suicide Severity Rating Scale (C-
SSRS), if this ideation occurred in the past 6 months prior to Screening, or “yes” on any 
item of the Suicidal Behavior section, except for the “Non-Suicidal Self-Injurious 
Behavior” in the past 2 years. (Section 4.2)

 

Because different sourcing strategies may be applied for glatiramer acetate depending on 
the country and because this control treatment is unblinded to the dispensing pharmacist 
and treating physician, medication numbering was removed as a requirement for the label 
for glatiramer acetate. (Section 5.1)

The description of study drug storage specifies that all study drug is to be stored 
refrigerated. (Section 5.5.3)

Management of patients with bradycardia following the first dose of fingolimod was 
changed to require overnight monitoring and second dose monitoring only if the patient 
was treated for the bradycardia. Patients experiencing prolonged QTc at 6 hours after first 
 


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dose of fingolimod are required to be monitored overnight and second dose monitoring is 
required. (Section 5.5.5)

A statement was added in Section 5.5.9 to clarify that fingolimod may be restarted after a 
patient receives a live or live attenuated vaccine.

Additional diabetes-specific baseline characteristics will be collected in patients with 
diabetes. (Section 6.2)

The qualifications of the rater of the Expanded Disability Status Scale were clarified. 
(Section 6.4.2)

A dermatological examination will be performed at Screening, 12 months, end of 
treatment, and end of study to identify new skin lesions. (Table 6-1, Table 6-2, Section 6.5, 
Section 6.5.10, and Section 9.5.2) 

Systolic and diastolic blood pressure will be measured in the supine position followed by 
measurements with the patient standing, with documentation of orthostatic hypotension if 
it occurs. (Section 5.5.5 and Section 6.5.2)

Discharge criteria following first dose have been expanded to include review of ECG for 
AV block, prolonged QTc, and decreasing heart rate. They also include requirement for 
overnight hospitalization in the event that pharmacologic intervention is required during 
first dose observation period or for prolonged QTc. (Section 5.5.5)

The requirement for restarting study drug and on-site monitoring after fingolimod 
interruption and restarting was changed. (Section 5.5.6)

 

Direction was added that the central laboratory will only report hematology absolute 
counts of eosinophils, basophils, and monocytes to maintain site blinding. The central 
laboratory will only report absolute total white blood cell, neutrophil, and lymphocyte 
counts to the site in case of a clinically notable abnormality. (Section 6.5.3.1)

Body weight will be assessed at each visit to identify weight gain that may be indicative of 
edema. (Table 6-1, Section 6.5.2, Appendix 1)

A footnote was added to Table 6-1 and Table 6-2 and text was added in Section 6.5.2
clarifying at which visits body temperature is to be measured.

An additional ophthalmological examination will be performed at 6 months of treatment. 
(Table 6-1)

Wording was added to clarify that blood samples are to be in the fasted state at the 
screening visit and to clarify that blood samples at subsequent visits are recommended to 
be in the fasted state. (Section 6.5.3)

HbA1c will be included in all chemistry assessments. (Section 6.5.3.2)

Uric acid and bicarbonate will be included in the serum chemistry assessments. 
(Section 6.5.3.2)

Urinalysis will be performed at all visits. Procedures have been added to follow-up edema, 
weight gain, or proteinuria with additional urinalysis and follow-up by nephrologist if 
protein/creatinine ratio is abnormal. (Table 6-1, Table 6-2, and Section 6.5.3.3)
 


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
Patients who experience new significant cardiac symptoms or symptoms of pulmonary 
hypertension are to be referred to a specialist for further diagnostic workup. 
(Section 6.5.1)

 

Pulmonary function tests (PFTs), including forced expiratory volume in 1 second (FEV1), 
forced vital capacity (FVC), and diffusion capacity of carbon monoxide (DLCO), will be 
performed at Screening, Month 6, Month 12, end of study, and 3 months after study drug 
discontinuation. (Table 6-1, Table 6-2, Section 6.5.9, Section 9.5.2, and References) 
Guidance for monitoring pulmonary function is provided in Appendix 3.

Patients who are withdrawn from the study because of a respiratory adverse event(s) 
should be evaluated by a pulmonary specialist and further investigations (PFTs, chest 
x-ray or high-resolution computed tomography [HRCT], biopsy) as needed. (Section 6.5.9
and Section 7.1)

The C-SSRS will be administered using an interactive voice response system (IVRS) at 
Screening and at every study visit after randomization. (Table 6-1, Table 6-2, 
Section 6.5.11, and Section 9.5.2)

 
 

Patients experiencing an ischemic or thrombotic adverse event are to be referred to a 
specialist for a diagnostic workup and management. (Section 7.1)

Laboratory specimens that are not in association with a regular study visit are to be sent to 
the central laboratory for analysis and inclusion of the data in the study data sets. 
(Section 7.1)

 

Notable values for additional laboratory assessments have been added to Appendix 1
(Clinically notable laboratory values and vital signs), and some notable values were 
changed.

Previous Appendix 3 was deleted because exclusion criterion referring to this appendix 
was deleted.

Appendix 3 was revised to require discontinuation of study drug if clinical symptoms of 
infection accompany lymphopenia. Discontinuation of study drug for lymphopenia in the 
absence of clinical signs of infection is at the discretion of the investigator. 

Appendix 3 was revised to require discontinuation of study drug in patients receiving 
glatiramer acetate who develop significant lymphopenia.

Appendix 4 was revised to include guidance on ophthalmic monitoring of patients with 
any visual disturbances while on therapy and in patients with diabetes mellitus or uveitis.
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities.
 


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The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
 


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Protocol synopsis
Title of study: A 12-month, randomized, rater- and dose-blinded study to compare the efficacy and 
safety of fingolimod 0.25 mg and 0.5 mg administered orally once daily with glatiramer acetate 20 mg 
administered subcutaneously once daily in patients with relapsing-remitting multiple sclerosis
Purpose and rationale: The purpose of this study is to compare the efficacy and safety of fingolimod 
0.50 mg and fingolimod 0.25 mg to glatiramer acetate (20 mg) for the treatment of patients with 
relapsing-remitting multiple sclerosis (RRMS) as part of a postapproval commitment for the FDA.
 
 
 
Objectives:
Primary Objective:
The primary objective is to demonstrate that at least 1 dose (tested hierarchically 0.5 mg followed by
0.25 mg) of fingolimod is superior to glatiramer acetate 20 mg subcutaneous (SC) in reducing the 
annualized relapse rate (ARR) up to 12 months in patients with relapsing-remitting MS.
Secondary Objectives:
To evaluate in fingolimod 0.5 mg, fingolimod 0.25 mg, and glatiramer acetate 20 mg groups:

the change from Baseline in brain volume at Month 12 or end of study

the number of active T2 lesions (new or newly enlarging lesions compared with Baseline) at 
Month 12 or end of study.

the proportion of patients free of new or newly enlarging T2 lesions compared to Baseline at 
Month 12 or end of study

the change from Baseline in T2 lesion volume at Month 12 or end of study

the change from Baseline in the number and volume of T1 hypointense lesions at Month 12 
or end of study

the number and volume of gadolinium (Gd)-enhancing T1 lesions at Month 12 or end of study

the safety and tolerability up to Month 12

the change from baseline in treatment satisfaction as measured by the Treatment Satisfaction 
Questionnaire for Medication (TSQM) at Month 12 or end of study
 


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Population: 
The study population will consist of adult male and female patients with RRMS. Treatment-naïve 
patients and patients previously treated with disease-modifying therapies for MS, with the exception of 
S1P modulator therapy, are eligible to participate in the study. The anticipated total number of patients 
to be screened is approximately 2610, with approximately 1960 patients randomly assigned to study 
treatment.
Key Inclusion/Exclusion criteria:
Inclusion criteria:
1.
Written informed consent must be obtained before any assessment is performed 
2.
Male and female patients 18 to 65 years of age, inclusive.
3.
Patients with RRMS, as defined by 2010 revised McDonald criteria.
4.
Patients must be neurologically stable with no onset of relapse within 30 days of 
randomization.
5.
Patients with at least 1 documented relapse during the previous year or 2 documented 
relapses during the previous 2 years before randomization.
6.
Patients with an Expanded Disability Status Scale (EDSS) score of 0 to 6.0, inclusive, at 
Screening. A score of 6.0 indicates unilateral assistance (cane or crutch) required to walk at 
least 100 meters with or without resting.
Exclusion criteria:
1.
Patients with a history of malignancy of any organ system (other than cutaneous basal cell 
carcinoma) in the last 5 years that do not have confirmation of absence of a malignancy prior 
to randomization.
2.
Patients with an active chronic disease (or stable but treated with immune therapy) of the 
immune system other than MS (e.g., rheumatoid arthritis, scleroderma, Sjogren’s syndrome, 
Crohn’s disease, ulcerative colitis) or with a known immunodeficiency syndrome 
(HIV-antibody positive, AIDS, hereditary immune deficiency, drug-induced immune 
deficiency).
3.
Patients who have been treated with: 

Intravenous (IV) immunoglobulin (Ig) within 4 weeks before randomization

Immunosuppressive/chemotherapeutic medications (e.g., azathioprine, 
cyclophosphamide, methotrexate) within 6 months before randomization

Natalizumab within 2 months before randomization

Previous treatment with lymphocyte-depleting therapies (e.g., rituximab, alemtuzumab, 
ofatumumab, ocrelizumab, or cladribine) within 1 year before randomization

Previous treatment with mitoxantrone within 6 months before randomization

Use of teriflunomide within 3.5 months prior to randomization, except if active washout 
(with either cholestyramine or activated charcoal) was done. In that case, plasma levels 
are required to be measured and be below 0.02 mg/L before randomization
 


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No washout period is necessary for patients treated with dimethyl fumarate, interferon 
(IFN) beta, or glatiramer acetate.  
Patients being treated with dimethyl fumarate, glatiramer acetate, or IFN beta at the 
Screening visit can continue drug intake up to the day before Day 1 of this study (i.e., 
there is no need for a washout period).
4. Patients who have been treated with systemic corticosteroids or adrenocorticotropic hormones 
in the past 30 days prior to the screening magnetic resonance imaging (MRI) procedure.
5. Patients with uncontrolled diabetes mellitus (glycosylated hemoglobin >9%) or with diabetic 
neuropathy.
6. Patients with a diagnosis of macular edema during Screening (patients with a history of 
macular edema will be allowed to enter the study provided that they do not have macular 
edema at Screening).
7. Patients with severe active bacterial, viral, or fungal infections.
8. Patients without acceptable evidence of immunity to varicella zoster virus (VZV) at 
randomization (See Appendix 3 for guidance on acceptable evidence of immunity and 
requirement for serologic testing).
9.
Patients who have received any live or live-attenuated vaccines (including VZV, herpes 
simplex, or measles) within 1 month before randomization.
10. Patients who have received total lymphoid irradiation or bone marrow transplantation.
11. Patients with any unstable medical/psychiatric condition, as assessed by the primary treating 
physician at each site.
12. Patients who in the last 6 months experienced any of the following cardiovascular conditions 
or findings in the screening electrocardiogram (ECG): myocardial infarction, unstable angina, 
stroke, transient ischemic attack or decompensated heart failure requiring hospitalization or 
Class III/IV heart failure.
Investigational drug:

Fingolimod (FTY720) 0.5-mg capsules for oral administration once daily

Fingolimod (FTY720) 0.25-mg capsules for oral administration once daily
Both strengths of fingolimod capsule will be identical in appearance and will be packaged in identical 
bottles.
Control drug:
Glatiramer acetate 20-mg SC injection once daily.
Study design:
This is a multicenter, randomized, rater- and dose-blinded study to compare the efficacy and safety of 
0.25 mg and 0.5 mg of fingolimod with glatiramer acetate 20 mg SC in patients with RRMS. 
This study will consist of 3 periods:

Screening Period: up to 45 days for all patients

Treatment Period: 12 months of glatiramer acetate 20 mg, fingolimod 0.25 mg, or fingolimod 
0.5 mg

Follow-up Period will occur 3 months (12 weeks) after the last dose of study drug for all 
patients
After signing the informed consent, patients will enter the Screening Period to determine eligibility for 
the study. After inclusion/exclusion criteria are reviewed again and after safety assessments are 
conducted, patients will enter the Treatment Period and will be randomly assigned into one of three
groups (for details about the randomization see Section 9.6 - Sample size calculation):

Group 1 will receive fingolimod 0.5 mg orally once a day for up to 12 months

Group 2 will receive fingolimod 0.25 mg orally once a day for up to 12 months
 


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
Group 3 will receive glatiramer acetate 20 mg subcutaneously once a day for up to 12 months
Patients will take their first dose of study drug at Visit 2. Thereafter, patients in each fingolimod 
treatment arm will take 1 capsule orally once a day for 12 months. Patients in the glatiramer acetate 
treatment arm will self-administer an SC injection of 20 mg of glatiramer acetate once a day for 
12 months. In order to ensure patient safety 6-hour first dose monitoring procedures are to be followed 
for patients receiving fingolimod. First-dose monitoring is to be conducted by the primary treating 
physician.
Starting at Visit 3/Month 1, all visits in the Treatment Period have a visit window of ±5 days. At 
Visit 7/end of treatment (EOT)/Month 12, the study staff should complete the study completion 
electronic case report form (eCRF).
The end-of-study follow-up visit will occur 3 months (12 weeks) after the last dose of study drug 
administration (for patients who complete the study and for patients who prematurely discontinue the 
study).
Efficacy assessments: 

MS ARR

Magnetic resonance imaging (MRI)


Safety assessments:

Physical and neurological examination

Vital sign measurements

Laboratory evaluations

ECG results

Ophthalmologic examinations

Pulmonary function tests

Dermatological examination

Columbia-Suicide Severity Rating Scale
Quality of life assessments:

Patient-reported outcomes for multiple sclerosis (TSQM, 
)
Data analysis:
The primary outcome is the ARR which is defined as the average number of confirmed relapses per 
year (i.e., the total number of confirmed relapses divided by the total days in the study multiplied by 
365.25). For the primary analysis, the number of relapses will include all the confirmed relapses 
experienced during the study. The time spent in the study will correspond to the observation period for 
all the relapses from first dose on study drug to end of study.
The 2 doses of fingolimod will be tested hierarchically versus glatiramer acetate in a step-down 
procedure. For each of the 2 fingolimod doses, the null hypothesis is that there is no difference in the 
ARRs between patients treated with fingolimod and patients treated with glatiramer acetate versus the 
alternative hypothesis that there is a difference between the 2 treatment groups. The null hypothesis 
will be rejected if the observed P value for the between-treatment comparison is less than the 
significance level as specified in multiplicity adjustment procedure.
 


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H01: µ FTY 0.5 mg=µ glatiramer acetate versus HA1: µ FTY 0.5 mg≠µ glatiramer acetate 
H02: µ FTY0.25 mg=µ glatiramer acetate versus HA2: µ FTY0.25 mg≠µ glatiramer acetate 
No formal hypothesis will be tested between the 2 fingolimod doses because the study is not powered 
to detect a difference in treatment effect between these doses.
The hypotheses will be tested using a negative binomial regression model with log link, using 
treatment, number of relapses in the previous year before study enrollment, baseline EDSS, and 
baseline number of Gd-enhancing T1 lesions and country (or region) as covariates. In the analysis, the 
response variable is the number of confirmed relapses for each patient. The patient’s time in the study 
(natural log of time in years) is used as an offset variable to obtain the ARR, adjusted for the varying 
lengths of patient’s time in the study (time in years). The treatment effect of fingolimod doses versus 
glatiramer acetate will be presented as an ARR ratio with corresponding 95% confidence intervals and 
p values. 
To adjust for multiple testing in this study, a step-down hierarchical testing procedure will be used. 
There are 2 hypotheses being tested (H01, H02). Because it is highly likely that the approved dose of 
fingolimod (0.5 mg) is more efficacious than the lower dose (0.25 mg), the approved dose of 
fingolimod is initially tested against glatiramer acetate at a 2-sided significance level of 0.05. Only if 
this initial test H01 is rejected will H02, the low dose of fingolimod, be tested against glatiramer acetate 
also at a 2-sided significance level of 0.05.
The sample size calculations and power considerations follow the method outlined in Keene et al.,
2007 with a constant dispersion parameter k (k=0.2231). The power of the study was evaluated under 
various ARR assumptions and various dropout patterns based on the cumulative literature on 
glatiramer acetate and the Novartis data on fingolimod. The anticipated ARR for patients treated with 
0.5 mg fingolimod is µFTY 0.5 mg=0.195, the ARR for those treated with glatiramer acetate is 
µglatiramer acetate=0.30. Therefore, the estimated ARR reduction for fingolimod 0.5 mg versus glatiramer 
acetate is 35%. Assuming a dropout rate of 15% based on data from this D2312 study (status 
Feb-2015), the total 1960 randomized patients with approximately 847 patients in the fingolimod 
0.25-mg group, 615 patients in the fingolimod 0.5-mg group, and 498 patients in the glatiramer acetate 
20-mg group will achieve approximately 90% statistical power for the comparison of fingolimod 0.5 mg 
versus glatiramer acetate at a 2-sided significance level of 0.05. This calculation takes into account 
that patients who discontinue prematurely from the study can participate with partial data to the 
primary endpoint.
Fingolimod 0.25 mg has never been studied in a clinical trial in MS. Based on PK/PD modeling results, 
it is anticipated that the ARR in patients treated with fingolimod 0.25 mg is approximately 15% higher 
than in those treated with fingolimod 0.5 mg. In line with the PK/PD modeling, the anticipated ARR in 
patients treated with fingolimod 0.25 mg is µFTY 0.25 mg=0.225, which corresponds to a 25% reduction in 
ARR in patients treated with fingolimod 0.25 mg compared to those treated with glatiramer acetate. 
Following the multiplicity adjustment procedure, the power to detect a 25% reduction in ARR for 
patients treated with fingolimod 0.25 mg compared with patients treated with glatiramer acetate is 
approximately 68% at a 2-sided significance level of 0.05, if the primary objective for the fingolimod 
0.5-mg dose can be rejected first. A formal comparison between the two fingolimod doses is not 
intended, as the study is not powered for such a comparison.
The statistical software R (Version 2.13.1, open source) and the R library packages “MASS” and 
“PSCL” were used for sample size calculations and power analysis.
 


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1
Introduction
1.1
Background
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous 
system (CNS) causing pronounced neurological disability in young adults, primarily women, 
with disease onset typically occurring between the ages of 20 and 40 years. The approximate 
prevalence rate of MS in the United States is 400,000 (0.1%). 
Typically recurrent acute episodes (relapses) of neurological symptoms, which are followed 
by a complete or partial recovery, can be observed during the relapsing-remitting multiple 
sclerosis (RRMS) disease course. Approximately 50% of these patients progress to secondary 
progressive MS (SPMS) within 10 years and 90% within 25 years. Apart from these initially 
relapsing forms of MS, 10% to 15% of patients present with primary progressive MS (PPMS), 
which is characterized by steady deterioration of impairment without prior experience of 
relapses (Keegan et al, 2002).
Fingolimod (FTY720) Gilenya® is an oral, once-daily immunomodulatory drug that has been 
approved for the treatment of relapsing MS in the United States, Europe, and other countries. 
Pharmacologically, 
fingolimod, 
after 
phosphorylation 
to 
fingolimod-phosphate 
(fingolimod-P) targets a class of G protein-coupled receptors, which bind the pleiotropic 
sphingolipid mediator sphingosine 1-phosphate (S1P) and acts in large part by down-
modulating S1P/S1P receptor responses in the immune and the central nervous systems. It 
causes a reversible sequestration of a proportion of CD4+ and CD8+ positive T cells and
B cells from blood and spleen into lymph nodes and Peyer’s patches, apparently without 
affecting many of the functional properties of these cells. Under normal circumstances, T cells 
selectively require S1P1 activation for emigration from the thymus, and both T and B cells 
require this receptor for egress from peripheral lymphoid organs. Fingolimod-P acts as a 
super-agonist of the S1P1 receptor on lymphocytes, inducing its uncoupling/internalization 
and intracellular lysosomal degradation. The internalization and degradation of S1P1 renders 
these cells unresponsive to S1P, depriving them of the obligatory signal to egress from 
lymphoid organs and recirculate to peripheral inflammatory tissues. As a consequence, 
autoaggressive T cells remain trapped in the lymphoid system, i.e., in the autoantigen-draining 
cervical lymph nodes in experimental autoimmune encephalomyelitis MS, which reduces 
their recirculation to the CNS and abrogates central inflammation.
The lymphocytes trapped by fingolimod in the LNs contain the pro-inflammatory T-helper 
(CD4+) IL-17 producing lymphocyte subset (Th17): A T-helper subset which is derived from 
naïve T cells when these cells are stimulated in the presence TGF-β, IL-1β and IL-23. Th17 
cells manifest a phenotype of increased IL-17 production. Th17 cells have been shown to play 
an important role in the induction of autoimmune disease, but are crucial for the immune 
response against fungi and extracellular bacteria. Regulatory T-cells (Treg) are a subset of 
predominantly CD4+ T-cells differentiated from naïve T-cells in the periphery after 
stimulation with TGFβ and antigen (iTreg) or generated in the thymus (nTreg); other 
regulatory T-cell subtypes exist, including CD8+ Tregs. Tregs play an important role in the 
regulation of immune function and prevention of autoimmune disease. A balance between 
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In EAE, among other T-cells, Th17 cells transmigrate efficiently across the blood-brain-
barrier (BBB), disrupt BBB tight junctions, highly express granzyme B and kill human 
neurons, and promote CNS inflammation through additional CD4+ T-cell recruitment (Kebir 
2007). Accordingly, large numbers of Th17 cells are found in brain tissues from MS patients, 
particularly in acute and chronic active lesions (Tzartos 2008). Analysis of blood T-cells from 
fingolimod-treated MS patients now revealed strikingly reduced numbers of IL-17-producing 
Th17 cells in circulation (Mehling 2010), suggesting that fingolimod directly abrogates the 
inflammatory Th17 axis in MS.
Since fingolimod has a preferential impact on the levels of Th17 T-helper cells, the 
investigation of the counts and relative proportions of Th17 cells as compared to T-regulator 
(Treg) cells is of relevance for the determination of the effects of the drug on immune 
homeostasis, both in terms of immune defense as well as suppression of the auto-immunity.
In two Phase III studies in patients with RRMS fingolimod has demonstrated a significantly 
superior efficacy over current standard therapy with interferon (IFN) beta-1a intramuscular 
(IM) (standard of care) and over placebo, respectively:
In the one-year D2302 (TRANSFORMS) study in 1292 patients with RRMS, an active 
comparator trial against an established standard of care, fingolimod significantly reduced 
annualized relapse rates (ARR) by 52% (0.5 mg dose, ARR 0.21) and 38% (1.25 mg dose, 
ARR 0.26) vs. IFN beta-1a IM (ARR 0.43). These findings were supported by effects on 
disease activity as measured in brain magnetic resonance imaging (MRI) (Cohen et al, 2010).

Results from the 2-year placebo-controlled D2301 (FREEDOMS) study in 1272 patients 
with RRMS show that fingolimod reduced the relapse rate by 54% for the 0.5 mg dose 
(ARR 0.18) and 60% for the 1.25 mg dose (ARR 0.16) compared to placebo (ARR 0.40; 
both comparisons p<0.001). In addition, fingolimod reduced the risk of progression of 
disability by 30 - 37% for patients on 0.5 mg (p=0.024) and 32 - 40% for those on 1.25 mg 
(p=0.017) compared to placebo over two years. These findings were supported by positive 
effects on brain lesions as measured by MRI scan (Kappos et al, 2010).
The safety profile of fingolimod has been well characterized in the MS clinical development 
program. As of 29 February 2012, the MS clinical trials exposure in global and local studies is 
estimated to be approximately 16,500 patient-years in more than 10,000 MS patients. For 
updated exposure and safety information, please refer to current investigator brochure.
The safety profile observed in the fingolimod MS clinical development program can be 
summarized as follows:

The overall incidence of adverse events (AEs) leading to discontinuation of study drug in 
[Study CFTY720D2301] was comparable for the fingolimod 0.5 mg/day (7.5%) and 
placebo group (7.7%) but higher in the fingolimod 1.25 mg/day group (14.2%). The 
overall incidence of serious adverse events (SAEs) was comparable between fingolimod 
groups (11.9% and 10.1% for fingolimod 1.25 mg/day and fingolimod 0.5 mg/day, 
respectively) and placebo (13.4%).

Specific AEs that were reported more commonly in MS patients treated with fingolimod 
than placebo included elevations of liver enzymes, in particular increases in alanine 
aminotransferase (ALT) and γ-glutamyltransferase (GGT), reductions in white blood cell 
(WBC) counts (lymphocytes and total WBC count), transient bradycardia after the first 
 


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dose of fingolimod, macular edema, hypertension, dyspnea, bronchitis, and diarrhea. The 
AEs most prominently associated with fingolimod treatment (eg, liver enzyme elevations, 
bradycardia, and macular edema) appeared to show a dose response. There were no AEs 
that appeared to be specifically related to long-term treatment with fingolimod.

In general, the AE profile of fingolimod in MS patients did not depend on gender, age, or 
previous treatment with disease-modifying drugs. The only exception was liver enzyme 
elevations, which were more frequent in male patients than in female patients treated with 
fingolimod. 

The overall incidence of infections, including serious infections, was similar in the 
fingolimod treatment groups and the comparator arms (IFN or placebo) in both completed 
Phase III studies. A slightly higher frequency of lower respiratory tract infections 
(primarily bronchitis) was observed in fingolimod-treated patients, with an apparent dose 
effect. The current data showed no clear relationship between lymphocyte count and the 
incidence of infections on fingolimod treatment. 

The accumulated data from the MS program do not show an association of fingolimod 
therapy with the development of malignancies. In the FREEDOMS study, more cancers 
were seen in the placebo group than in the treated groups. Incidence estimates for various 
forms of skin cancer (and other malignancies) from pooled safety data are comparable 
between treatment groups and placebo. There appears to be no increased risk with greater 
duration of exposure (Kappos et al, 2010).

Initiation of fingolimod treatment has been associated with atrioventricular (AV) 
conduction delays usually as first-degree AV blocks (prolonged PR interval on 
electrocardiogram [ECG]). Second-degree AV blocks, usually Mobitz Type I 
(Wenckebach), have been observed in less than 0.5% of patients receiving fingolimod 
0.5 mg in clinical trials. The conduction abnormalities typically were transient, 
asymptomatic, usually did not require treatment, and resolved within the first 24 hours on 
treatment.  

Data on the safe use of fingolimod in pregnancy or with breast-feeding are limited, 
although preclinical data suggest risk to the fetus and newborn is possible.
In the post-marketing setting, isolated delayed onset events, including transient asystole and 
the 1 unexplained death, within 24 hours of the first dose, have occurred. These events have 
been confounded by concomitant medication and/or pre-existing diseases and the relationship 
to fingolimod is uncertain. It is recommended that fingolimod not be administered to patients 
with a history of cardiovascular or cerebrovascular disease or to those patients taking heart-
rate lowering medication.
Glatiramer acetate consists of the acetate salts of synthetic polypeptides, containing 
4 naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine. The 
mechanisms by which glatiramer acetate acts in patients with MS are not fully understood. 
However, it is thought to act by modifying immune processes believed to be responsible for 
the pathogenesis of MS. This hypothesis is supported by findings of studies that have been 
carried out to explore the pathogenesis of experimental allergic encephalomyelitis.
Evidence supporting the effectiveness of glatiramer acetate (20 mg/day) in decreasing the 
frequency of relapses in patients with RRMS comes from 2 placebo-controlled studies. In a 
single centre study in 50 patients randomized equally to glatiramer acetate or placebo, the 
 


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average number of relapses per patient over 24 months was reduced from 2.7 on placebo to 
0.6 in the glatiramer acetate arm (Bornstein et al, 1987). In a larger placebo-controlled 
multicentre study in 251 patients a reduction of the 2-year relapse rate from 1.68 on placebo 
to 1.19 on glatiramer acetate was observed (Johnson et al, 2001). Results in both studies were
supported by beneficial effects of glatiramer acetate on MRI markers of inflammatory disease 
activity and on other relapse-related endpoints, as compared to placebo.
In addition, 3 trials comparing high-dose IFN with glatiramer acetate were conducted. In the 
REGARD (Rebif® versus glatiramer acetate in patients with RRMS) open-label study in 764 
patients equally randomized to the two treatment arms, there were no significant differences 
between groups treated with 44 µg of subcutaneous (SC) IFN β-1a 3 times a week and 20 mg 
of SC glatiramer acetate daily after 96 weeks of treatment in the time of the first relapse, the 
annualized relapse rate (IFN β-1a 0.30; glatiramer acetate 0.29), or magnetic resonance 
imaging (MRI) outcomes (number and change in volume of T2 active lesions) (Mikol et al, 
2008).
The dose-blinded BEYOND study (N = 2244 in a 1:2:2 ratio) compared 20 mg SC glatiramer 
acetate with 250 µg and 500 µg of SC IFN beta-1b every other day. Results showed that the 
ARR was similar between groups (IFN beta-1b SC 500 μg 0.33; IFN beta-1b SC 250 μg 0.36; 
glatiramer acetate 0.34), with no significant difference in the time of the first relapse or the 
proportion of patients remaining relapse free. For MRI data, there were no significant 
differences in gadolinium (Gd)-enhancing lesions, T1 lesions, or normalized brain volume 
between groups. There were significant differences in the cumulative number of new T2 
lesions between the patients treated with IFN and glatiramer acetate, favouring IFN 
(O’Connor et al, 2009).
In the BECOME study in 75 patients with RRMS, efficacy of treatment with IFN beta-1b and 
glatiramer acetate was assessed by monthly MRI and relapse rate for up to 2 years. There 
were no significant differences in the number of combined active lesions on MRI between the 
2 groups. Correspondingly, the ARR between the 2 treatment groups did not show significant 
differences (IFN beta-1b 0.37; GA 0.33) (Cadavid et al, 2009).
1.2
Purpose
The purpose of this study is to compare the efficacy and safety of fingolimod 0.50 mg and 
fingolimod 0.25 mg to glatiramer acetate (20 mg) for the treatment of patients with RRMS as 
part of a postapproval commitment for the FDA.
 
 
 
 


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2
Study objectives
2.1
Primary objective
The primary objective is to demonstrate that at least one dose (tested hierarchically 0.5 mg 
followed by 0.25 mg) of fingolimod is superior to glatiramer acetate 20 mg SC in reducing the 
ARR up to 12 months in patients with relapsing-remitting MS.
2.2
Secondary objectives
To evaluate in fingolimod 0.5 mg, fingolimod 0.25 mg, and glatiramer acetate 20 mg groups:

the change from Baseline in brain volume at Month 12 or end of study

the number of active T2 lesions (new or newly enlarging lesions compared with Baseline) 
at Month 12 or end of study.

the proportion of patients free of new or newly enlarging T2 lesions compared to Baseline 
at Month 12 or end of study

the change from Baseline in T2 lesion volume at Month 12 or end of study

the change from Baseline in the number and volume of T1 hypointense lesions at 
Month 12 or end of study

the number and volume of Gd-enhancing T1 lesions at Month 12 or end of study

the safety and tolerability up to Month 12

the change from baseline in treatment satisfaction as measured by the Treatment 
Satisfaction Questionnaire for Medication (TSQM) at Month 12 or end of study
 


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3
Investigational plan
3.1
Study design
This is a multicenter, randomized, rater- and dose-blinded study to compare the efficacy and 
safety of 0.25 mg and 0.5 mg of fingolimod with glatiramer acetate 20 mg SC in patients with 
 


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RRMS. Originally, approximately 2550 patients with RRMS were to be randomized, which 
has been reduced to a total of 1960 patients as per protocol amendment 2.
This study will consist of 3 periods:

Screening Period: up to 45 days for all patients

Treatment Period: 12 months of glatiramer acetate 20 mg, fingolimod 0.25 mg, or 
fingolimod 0.5 mg

Follow-up Period will occur 3 months (12 weeks) after the last dose of study drug for all 
patients
The study design is presented in Figure 3-1.
Figure 3-1
Study design
a. Follow-up will occur 3 months (12 weeks) after the last dose of study drug for all patients.
The assessment schedule is presented in Table 6-1. After signing the informed consent, 
patients will enter the Screening Period to determine eligibility for the study. After 
inclusion/exclusion criteria are reviewed again and after study assessments are conducted, 
patients will enter the Treatment Period and will be randomly assigned into one of the three
groups (for details about the randomization, see Section 9.6 - Sample size calculation):

Group 1 will receive fingolimod 0.5 mg orally once a day for up to 12 months

Group 2 will receive fingolimod 0.25 mg orally once a day for up to 12 months

Group 3 will receive glatiramer acetate 20 mg subcutaneously once a day for up to 
12 months
Patients will take their first dose of study drug at Visit 2. Thereafter, patients in each 
fingolimod treatment arm will take 1 capsule orally once a day for 12 months. Patients in the 
fingolimod 0.5
mg/day
Treatment Period
Screening 
Period
Day –45 to –1
glatiramer acetate 20
mg/day
Day 1 to Month 12
fingolimod 0.25
mg/day
Follow up 
Visita
Randomization
Month 15
 


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glatiramer acetate treatment arm will self administer an SC injection of 20 mg of glatiramer 
acetate once a day for 12 months. In order to ensure patient safety during the first dose 
administration, patients will take the first dose at the study sites and procedures in the protocol 
must be followed for all patients receiving oral capsules as outlined in the first-dose 
monitoring instructions (Section 5.5.5). First-dose monitoring is to be conducted by the 
treating physician.
Starting at Visit 3/Month 1, all visits in the Treatment Period have a visit window of ±5 days. 
Sites are encouraged to comply with this visit window as much as possible.
The end-of-study follow-up visit will occur 3 months (12 weeks) after the last dose of study 
drug administration (for patients who complete the study and for patients who prematurely 
discontinue study).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2
Rationale of study design
A randomized parallel-group design has been chosen as it provides an unbiased assignment to 
treatment and allows the direct comparison of efficacy, tolerability, and safety of the 
3 treatment arms. A double-blind design was considered not suitable for this study as it would 
require double-dummy treatment and thus daily sham injections for the two fingolimod arms. 
Daily sham injections for the majority of study patients in a study of 12-month duration are 
not considered to be ethical. 
The confirmation of relapses as the primary outcome measure by a blinded rater, and the dose 
blinding between the two doses of fingolimod, will provide sufficient protection against bias, 
as will the full blinding of all MRI endpoints. ARR has been selected as primary endpoint as it 
represents a clinically relevant measure of disease activity and allows determination of 
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3.3
Rationale of dose/regimen, duration of treatment
In previous Phase III studies in patients with RRMS, the doses of fingolimod 0.5 mg and 
fingolimod 1.25 mg were tested. Both doses showed similar efficacy in terms of relapse rate 
reduction, imaging parameters, and disability progression. The fingolimod 0.5-mg dose 
demonstrated a favorable safety profile compared with the fingolimod 1.25-mg dose based on 
the incidence of specific AEs of interest and the overall study drug discontinuation rate. 
The minimal effective dose may not have been identified in the clinical development program, 
although the exposure-response model based on the ARR and T2 lesion count suggests that 
fingolimod 0.5 mg lies at the inflection point of the dose-response curve and that further 
reduction of the dose would lead to a reduction in treatment effect. Based on discussions with 
the FDA, the sponsor agreed to conduct further efficacy and safety assessments using a lower 
dose of fingolimod, with the 0.25 mg dose being the agreed-upon dose to study.
A 1-year treatment duration is suitable to detect the anticipated differences in treatment effect 
on relapse rate between drugs in this study.
3.4
Rationale for choice of comparator
In this study, the efficacy and safety of fingolimod 0.25 mg and fingolimod 0.5 mg will each 
be compared to glatiramer acetate 20 mg SC. An active comparator with established efficacy 
has been chosen as control for this study since placebo treatment for a duration of 1 year is not 
considered ethically acceptable, given the availability of several disease-modifying drugs, 
including fingolimod, for treatment of the target population of this study.
Glatiramer acetate is the most commonly prescribed disease modifying drug (DMD) in the 
United States and several other countries. Therefore it represents an acceptable alternative to 
treatment with fingolimod and an appropriate comparator in this study.
 
 
3.5
Purpose and timing of interim analyses/design adaptations
Not applicable.
4
Population
The study population will consist of adult male and female patients with RRMS who meet all 
of the inclusion criteria and none of the exclusion criteria defined in Section 4.1 and 
Section 4.2, respectively. Treatment-naïve patients and patients previously treated with 
disease-modifying therapies for MS, with the exception of S1P modulator therapy, are eligible 
 


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to participate in the study. Patients being treated with first-line DMDs at the screening visit 
can continue drug intake up to the day before Day 1 of this study (i.e., there is no need for a 
washout period).
The original anticipated total number of patients to be screened was approximately 3190, with 
approximately 2550 patients randomly assigned to the study treatment arms in a ratio of 1:1:1 
under the assumption of a 20% screening failure rate. In protocol amendment 2, the 
anticipated total number of patients to be screened is reduced to approximately 2610. The 
screening failure rate is estimated to be 25% and a total of 1960 randomized patients are 
targeted. After the introduction of protocol amendment 2, and IRB approval at all sites in all 
countries, a new randomization ratio of 5:3:2 will be used for the 3 treatment arms of 
fingolimod 0.25 mg, fingolimod 0.5 mg, and glatiramer acetate 20 mg. 
Refer to Section 9.6 (Sample Size Calculations) for details.
The inclusion and exclusion criteria will be assessed at Screening and Randomization Visit 
(before patient is randomly assigned to treatment using an interactive voice response system 
[IVRS]). The results of all screening assessments must be available before randomization. A 
subject who is under screening but has not been enrolled due to failure to meet the inclusion 
criteria or failure to be randomized within the specified time per protocol, may be considered 
for re-screening if a change in the patient’s medical status or a modification of the study’s 
eligibility criteria makes the patient potentially eligible. Re-screening will be allowed on a 
case-by-case basis upon approval by the study Medical Monitor. A new informed consent 
form should be signed in case of re-screening and a new number will be assigned to the 
subject. The required re-screening procedures should be discussed with the Medical Monitor.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed  
 
2. Male and female patients 18 to 65 years of age, inclusive
3. Patients with RRMS, as defined by 2010 revised McDonald criteria (Appendix 2)
4. Patients must be neurologically stable with no onset of relapse within 30 days of 
randomization 
5. Patients with at least 1 documented relapse during the previous year or 2 documented 
relapses during the previous 2 years before randomization
6. Patients with an Expanded Disability Status Scale (EDSS) score of 0 to 6.0, inclusive, at 
Screening. A score of 6.0 indicates unilateral assistance (cane or crutch) required to walk 
at least 100 meters with or without resting.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Patients with a history of malignancy of any organ system (other than cutaneous basal cell 
carcinoma) in the last 5 years that do not have confirmation of absence of a malignancy 
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2. Patients with an active chronic disease (or stable but treated with immune therapy) of the 
immune system other than MS (e.g., rheumatoid arthritis, scleroderma, Sjogren’s 
syndrome, Crohn’s disease, ulcerative colitis) or with a known immunodeficiency 
syndrome (HIV-antibody positive, AIDS, hereditary immune deficiency, drug-induced 
immune deficiency).
3. Patients who have been treated with: 

Intravenous (IV) immunoglobulin (Ig) within 4 weeks before randomization.

Immunosuppressive/chemotherapeutic medications (e.g., azathioprine, 
cyclophosphamide, methotrexate) within 6 months before randomization.

Natalizumab within 2 months before randomization.

Previous treatment with lymphocyte-depleting therapies (e.g. rituximab, alemtuzumab, 
ofatumumab, ocrelizumab, or cladribine) within 1 year before randomization.

Previous treatment with mitoxantrone within 6 months before randomization.

Use of teriflunomide within 3.5 months prior to randomization, except if active 
washout (with either cholestyramine or activated charcoal) was done. In that case
plasma levels are required to be measured and be below 0.02 mg/L before 
randomization.
No washout period is necessary for patients treated with dimethyl fumarate, IFN beta, or 
glatiramer acetate. Patients being treated with dimethyl fumarate, glatiramer acetate, or 
IFN beta at the screening visit can continue drug intake up to the day before Day 1 of this 
study (i.e., there is no need for a washout period).
4. Patients who have been treated with systemic corticosteroids or adrenocorticotropic 
hormones in the past 30 days prior to the screening MRI procedure.
5. Patients with uncontrolled diabetes mellitus (glycosylated hemoglobin [HbA1c] >9%) or 
with diabetic neuropathy.
6. Patients with a diagnosis of macular edema during Screening (patients with a history of 
macular edema will be allowed to enter the study provided that they do not have macular 
edema at Screening).
7. Patients with severe active bacterial, viral, or fungal infections.
8. Patients without acceptable evidence of immunity to varicella zoster virus (VZV) at 
randomization (See Appendix 3 for guidance on acceptable evidence of immunity and 
requirement for serologic testing).
9. Patients who have received any live or live-attenuated vaccines (including for VZV, 
herpes simplex, or measles) within 1 month before randomization.
10. Patients who have received total lymphoid irradiation or bone marrow transplantation.
11. Patients with any unstable medical/psychiatric condition, as assessed by the primary 
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12. Patients who in the last 6 months experienced any of the following cardiovascular 
conditions or findings in the screening ECG:

Myocardial infarction 

Unstable angina

Stroke

Transient ischemic attack

Decompensated heart failure requiring hospitalization or Class III/IV heart failure
(Additional monitoring guidelines for patients with any pre-existing cardiovascular conditions 
are provided in Section 5.5.5.)
13. Patients with history or presence of a Mobitz Type II AV block, or a third-degree AV
block or sick sinus syndrome, unless patient has a functioning pacemaker.
14. Patients with baseline QTc interval >500 msec.
15. Patients receiving Class Ia (e.g., ajmaline, disopyramide, procainamide, quinidine) or 
Class III antiarrhythmic drugs (e.g., amiodarone, bretylium, sotalol, ibutilide, azimilide, 
dofetilide).
16. Patients with severe respiratory disease, pulmonary fibrosis, or Class III or IV chronic 
obstructive pulmonary disease, or with clinically significant lung pathology on chest x-ray. 
Patients with controlled asthma are allowed to enter the study.
17. Patients with any of the following hepatic conditions:

severe hepatic injury (Child-Pugh Class C)

total bilirubin greater than 2 times the upper limit of the reference range, unless in 
context of Gilbert’s syndrome

conjugated bilirubin greater than 2 times the upper limit of the reference range

aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 
2 times the upper limit of the reference range

alkaline phosphatase (AP) greater than 2 times the upper limit of the reference range

gamma glutamyl-transferase (GGT) greater than 2 times the upper limit of the 
reference range
18. Patients with a screening WBC count <3500/mm3 or lymphocyte count <800/mm3.
19. Patients with any of the following neurologic/psychiatric disorders:

history of substance abuse (drug or alcohol) in the past 5 years or any other factor (i.e., 
serious psychiatric condition) that may interfere with the patient’s ability to cooperate 
and comply with the study procedures

progressive psychiatric/neurological condition that may affect participation in the 
study
20. Patients who have received an investigational drug or therapy within 180 days or 
5 half-lives of randomization, whichever is longer.
21. Patients with a history of hypersensitivity to any of the study drugs, to drugs of similar 
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22. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
human chorionic gonadotropin laboratory test.
23. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, UNLESS they are using highly effective contraception during dosing 
with study treatment. Highly effective contraception includes:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least 6 weeks before taking study treatment. In case 
of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment.

Male partner sterilization (at least 6 months prior to Screening). For female patients on 
the study, the vasectomized male partner should be the sole partner for that patient.

Use of oral, injected, or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example, hormone vaginal ring or transdermal hormone contraception, placement of 
an intrauterine device or intrauterine system. 
Women are considered post-menopausal and not of child-bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to 
Baseline. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment is she considered not 
of child bearing potential.
24. Patients who have previously been treated with glatiramer acetate discontinued treatment 
due to lack of efficacy or tolerability.
25. Patients with a history of treatment with fingolimod.
26. Patients with a score of 4 or 5 on the Suicidal Ideation item of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) within 2 years of Screening, or any “yes” on the Suicidal 
Behavior item of the C-SSRS at Screening.
 


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5
Treatment
5.1
Investigational and control treatment
Investigational drug

Fingolimod (FTY720) 0.5 mg capsules for oral administration once daily

Fingolimod (FTY720) 0.25 mg capsules for oral administration once daily
Both strengths of fingolimod capsule will be identical in appearance and will be packaged in 
identical bottles. Medication labels will comply with the legal requirements of each country 
and be printed in the local language. The medication labels will supply the medication number 
and information on storage conditions.
Control drug

Glatiramer acetate 20 mg SC injection once daily. 
The medication labels will supply information on storage conditions.
5.2
Treatment arms
There are 3 treatment arms. In the study, patients will be randomized to fingolimod 0.5 mg, 
fingolimod 0.25 mg, or glatiramer acetate 20 mg (for details about the randomization, see 
Section 9.6 – Sample size calculation).
5.3
Treatment assignment
At the Randomization Visit, all eligible patients will be randomized via interactive voice 
response system (IVRS) to 1 of the three treatment arms. The investigator, who is usually the 
treating physician or his /her delegate, will contact the IVRS after confirming that the patient 
fulfills all the inclusion/exclusion criteria. The IVRS will assign a randomization number to 
the patient, which will be used to link the patient to a treatment arm and will specify a unique 
medication number for the first package of study drug to be dispensed to the patient. The 
randomization number will not be communicated to the caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IVRS provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of 
 using a validated system that automates the random assignment of 
medication numbers to study drug packs containing each of the study drugs. 
The randomization scheme for patients will be reviewed and approved by 
 Biostatistics 
randomization team.
 


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5.4
Treatment blinding
In order to maintain rater-blinding, all efficacy assessments will be obtained by an 
Independent Evaluating Physician who must not otherwise be involved with any aspects of 
patient care and management. Patient care and management and other aspects of the conduct 
of the study at the study site will be under the responsibility of the Treating Physician.
The independent evaluating physician will remain blinded until the database lock and data 
analysis has been completed. In order to maintain rater-blinding, all patients will be instructed 
to wear appropriate clothing to completely cover typical or actual injection sites before all 
scheduled visits and relapse-related neurologic examinations, and not to discuss their 
treatment or AEs (e.g., injection site reactions) with the independent evaluating physician. 
These instructions will also be included on the appointment reminder cards. This procedure is 
essential to maintain the blinding of the efficacy assessments during the study. The treating 
physician and all other study staff should not discuss study treatment or AEs with the 
independent evaluating physician in order to maintain the “rater blind.” 
All patients receiving injections will be known to the treating physician to be in the glatiramer 
acetate treatment arm, therefore, only patients receiving oral study drug will require first dose 
safety monitoring visit to be performed by the treating physician.
To maintain blinding of treatment assignment, all patients will receive the same cooling bag 
to carry study drug.
Because of the extended duration of first-dose monitoring of patients receiving fingolimod, it 
is recommended that first-dose monitoring is performed, as far as possible, in a manner that 
prevents blinded site personnel from becoming aware of the duration of the monitoring period.
In order to maintain the blind for Novartis 
 staff, manual review of data listings that 
could potentially unblind personnel will be performed by reviewers who are independent of 
the study team.
5.5
Treating the patient
5.5.1
Patient numbering
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis 
 to the investigative 
site. Upon signing the informed consent form, the patient is assigned a patient number by the 
investigator. At each site, the first patient is assigned patient number 1, and subsequent 
patients are assigned consecutive numbers (e.g., the second patient is assigned patient 
number 2, the third patient is assigned patient number 3). The investigator or his/her staff will 
contact the IVRS and provide the requested identifying information for the patient to register 
them into the IVRS. Only the assigned patient ID will be uploaded automatically in the 
database. Once assigned to a patient, the patient number will not be reused. If the patient fails 
to be randomized for any reason, the IVRS must be notified as far as possible within 2 days 
that the patient was not randomly assigned. The reason for not being randomized will be 
entered on the screening log, and the demography eCRF should also be completed.
 


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5.5.2
Dispensing the study treatment
Each study site will be supplied with study drug for each treatment arm. One component of 
the packaging has a 2-part label. 
For fingolimod, each part of the label contains a medication number. At all drug dispensation 
visits, investigator staff will identify the fingolimod study drug package to dispense to the 
patient by calling the IVRS and obtaining the medication number. 
In countries where the label contains a medication number, site staff will identify the 
glatiramer acetate study drug package to dispense to the patient by calling the IVRS and 
obtaining the medication number. In countries where the glatiramer acetate label does not 
contain a medication number, glatiramer acetate will be dispensed from bulk stock at the site. 
The IVRS will still be involved in tracking dispensation of glatiramer acetate study drug.
Immediately before dispensing the package to the patient, investigator staff will detach the 
outer part of the label from the packaging and affix it to the source document (drug label 
form) containing that patient’s unique patient number.
5.5.3
Supply, storage, and tracking of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access. Upon receipt, all study drugs should be stored refrigerated 
according to the instructions specified on the drug labels. Clinical supplies are to be dispensed 
only in accordance with the protocol.
Medication labels will be in the local language and will comply with the legal requirements of 
each country. They will include storage conditions for the drug but no information about the 
patient except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Monitoring of drug accountability will be performed by 
the 
 field monitor during site visits and at the completion of the trial. Patients will be 
asked to return all unused study drug and packaging at the end of the study or at the time of 
study drug discontinuation. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to the 
 monitor or to the address provided in the 
investigator folder at each site.
Blinded study drug (fingolimod) and glatiramer acetate will be provided to the study centers; 
no study drug will need to be purchased locally. Fingolimod and glatiramer acetate should be 
stored in a limited-access area, according to the instructions on the study drug label. 
5.5.4
Instructions for prescribing and taking study treatment
The study drugs (fingolimod 0.5-mg and 0.25-mg capsules and glatiramer acetate 20 mg) will 
be dispensed at the randomization visit (Visit 2). Drug will then be dispensed at scheduled 
Visits 3, 4, 5, and 6. 
 


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At Visits 2, 3, 4, 5, and 6, patients randomly assigned to fingolimod 0.25 mg or 0.5 mg will 
receive a bottled supply of oral medication containing a sufficient number of capsules until 
their next scheduled visit. At Visits 2, 3, 4, 5, and 6, patients randomly assigned to glatiramer 
acetate will receive a package containing a sufficient number of prefilled syringes to last until 
their next scheduled visit.
The fingolimod study drug needs to be taken once a day with or without food. Glatiramer 
acetate needs to be injected subcutaneously once a day. All study drugs should be 
administered preferably at the same time each day.
Site personnel will need to provide training to the patients or caregivers on the correct 
procedure for administration of SC injections. A patient leaflet will be provided with each 
supply of study drug. The patient leaflet describes information related to the study drug 
including: storage information, precautions, and instructions for administering SC injections. 
This information should be reviewed with the patients to ensure that they understand the 
correct procedure.
Once the eligibility of a patient for entry into the Treatment Period has been confirmed based 
on the study inclusion/exclusion criteria, the site will contact the IVRS to obtain a 
randomization number to identify study drug. Before administration of the first dose of the 
study drug, the investigator should reconfirm a list of concomitant medications taken by the 
patient. 
The first dose of study drug is administered at the randomization visit (Visit 2). The treating 
physician will monitor the first dose intake in the clinic for at least 6 hours or longer if 
discharge criteria are not met in those patients receiving oral study drug (fingolimod) (see 
Section 5.5.5 for guidance for monitoring of patients taking their first dose of the study drug). 
Patients receiving injectable study drug do not require prolonged monitoring in the clinic after 
the first dose.
Throughout the study, careful planning of patient visits is required to make sure that the 
patients will have enough study drug to last until the next scheduled visit.
The investigator and study personnel should promote compliance by instructing the patient to 
take the study drug exactly as prescribed and by stating that compliance is necessary for the 
patient’s safety and for the validity of the study. The patient should be instructed to contact 
the site if he or she is unable for any reason to take the study drug as prescribed.
All doses prescribed and dispensed to the patient and all dose interruptions during the study 
will be recorded in the IVRS and drug administration record in the eCRF.
5.5.5
Guidelines for monitoring patients taking their first dose of fingolimod 
The patient will stay at the site for a minimum of 6 hours after the first dose of fingolimod to 
be monitored for signs and symptoms of bradycardia. All fingolimod patients will have an 
ECG performed prior to dosing and at the end of the 6-hour monitoring period. (Glatiramer 
acetate patients will have a single ECG during the randomization visit.) The treating physician 
is responsible for monitoring the patient following the first intake of fingolimod, as well as 
managing bradycardia symptoms should they occur. He or she must review vital signs during 
the 6-hour monitoring, post-dose ECG and assess discharge criteria at 6 hours after dosing. 
 


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Baseline or predose ECG should be provided by the site and be available for comparison to 
the postdose ECG in order to determine if discharge criteria are met. 
Heart rate and blood pressure should be measured before the first dose of fingolimod, then 
every hour for at least 6 hours thereafter (by the treating physician or an assisting nurse). 
Blood pressure will be measured in the supine position and then the standing position at each 
time point. When obtaining the predose heart rate before the first dose, the patient should be 
allowed to rest in the supine position for 5 minutes before taking the heart rate. The heart rate 
and blood pressure measurements should be repeated twice to produce 3 baseline readings in 
the supine position for both heart rate and blood pressure (before the first dose of fingolimod 
only). Heart rate and blood pressure will then be measured in the same manner (i.e., 3 baseline 
readings) with the patient in the standing position before the first dose of fingolimod. For 
comparison to the postdose heart rate values, the lowest predose supine value and lowest 
predose standing value of heart rate should be used. Patients should receive the first dose of 
fingolimod before 12:00 PM (noon) in the outpatient setting.
Patients may be discharged after 6 hours ONLY if ALL of the following criteria are met:

supine heart rate must be at least 45 beats per minute

heart rate must not be the lowest hourly value measured during the observation period 
(which would suggest that nadir may not have been reached)

patients must have no symptoms associated with decreased heart rate or must not have 
received treatment for bradycardia

ECG at 6 hours after dosing should not show any new significant abnormalities 
(e.g., onset second-degree or third-degree AV block, QTc ≥500 msec) other than sinus 
bradycardia, that were not also observed at the patient’s predose ECG
If the discharge criteria listed above are not met after 6 hours, observation must be continued 
until symptoms resolve. 
If a patient requires treatment for bradycardia/bradyarrhythmia during the first dose 
observation, the patient should be monitored overnight, and the 6-hour monitoring procedure 
should be repeated for the second dose of study drug. 
If a patient experiences a QTc interval greater than or equal to 500 msec at 6 hours after the 
first dose, the patient should be monitored overnight, and the 6-hour monitoring procedure 
should be repeated for the second dose of study drug.
Patients with some pre-existing conditions (e.g., ischemic heart disease, history of myocardial 
infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, 
uncontrolled hypertension, history of symptomatic bradycardia, history of recurrent syncope, 
severe untreated sleep apnea, AV block, sinoatrial heart block) may poorly tolerate the 
fingolimod-induced bradycardia, or experience serious rhythm disturbances after the first dose 
of fingolimod. Prior to treatment with fingolimod, these patients should have a cardiac 
evaluation by a physician appropriately trained to conduct such evaluation, and, if treated with 
fingolimod, should be monitored overnight with continuous ECG in a medical facility after 
the first dose.
Since initiation of fingolimod treatment results in decreased heart rate and may prolong the 
QT interval, patients with a prolonged QTc interval (>450 msec males, >470 msec females) 
 


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before dosing or during a 6-hour observation period, or at additional risk for QT prolongation 
(e.g., hypokalemia, hypomagnesemia, congenital long-QT syndrome), or on concurrent 
therapy with QT-prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, 
chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with 
continuous ECG in a medical facility.
Experience with fingolimod is limited in patients receiving concurrent therapy with drugs that 
slow heart rate or AV conduction (e.g., beta blockers, heart rate lowering calcium-channel 
blockers such as diltiazem or verapamil, or digoxin). Because the initiation of fingolimod 
treatment is also associated with slowing of the heart rate, concomitant use of these drugs 
during fingolimod initiation may be associated with severe bradycardia or heart block. The 
possibility of switching to drugs that do not slow the heart rate or AV conduction should be 
evaluated by the physician prescribing these drugs before initiating fingolimod. Patients who 
cannot switch should have overnight continuous ECG monitoring after the first dose. 
In addition to protocol mandated safety assessments and monitoring procedures, additional 
assessments may be required as per local prescribing information and should be followed 
accordingly. 
Patients should have written instruction on when to return to clinic and a 24-hour contact 
phone number to call in the event of any new or warranted symptoms (e.g., chest pain, 
dizziness, palpitations, syncope, nausea, vomiting). Patients should be instructed not to drive 
on the same day after the first dose of fingolimod administration.
Recommendations for management of bradycardia 
Prior to the administration of study drug, if, in the opinion of the investigator, the patient’s 
cardiovascular condition or medical history carry a significant risk for study participation, the 
patient should not be enrolled in the study, and the advice of a cardiologist should be sought. 
Atropine (SC or IV) is recommended as the first line treatment of bradycardia, up to a 
maximum daily dose of 3 mg.
Furthermore, the common guidelines for treatment of bradycardia (e.g., ACLS guidelines) 
should be followed as appropriate:

In case of clinical symptoms or hypotension, administration of atropine 1 mg, repeated 
administration in 3-5 minutes

If heart rate and/or blood pressure remains unresponsive, consider administration of 
dopamine drip 5-20 ug/kg/min or epinephrine drip 2-10 ug/min

Performance of transcutaneous pacing may also be considered
In the setting of decreased blood pressure, isoproterenol should be avoided/used with caution.
5.5.6
Permitted dose adjustments and interruptions of study treatment
Dose adjustments will not be allowed; however, drug interruptions will be allowed based on 
the judgment of the investigator. If an investigator determines that study drug should be 
stopped, then the SC injections or oral capsules, respectively, need to be stopped. Conditions 
or events that may lead to study drug interruptions based on investigator judgment and overall 
clinical assessment are:
 


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
SAE

emergency medical condition or unplanned hospitalization involving the use of prohibited 
medications (Section 5.5.9)

abnormal laboratory value(s) or abnormal test or examination result(s) (e.g., ECG values, 
ophthalmic findings). See Appendix 3 and Appendix 4 for guidance on monitoring of 
patients with specific test abnormalities

hypersensitivity to the study drug

patient noncompliance

vaccination
The 6-hour monitoring procedure when restarting study drug is mandatory in the following 
cases:

the treatment lasted for 14 days or less and was interrupted for 1 day or more, or

the treatment lasted for more than 14 days and less than 29 days and was interrupted for
more than 7 consecutive days, or

the treatment lasted for 4 weeks or more and was interrupted for more than 14 consecutive 
days.
Should a patient randomized to one of the fingolimod treatment arms interrupt the study drug 
as described above and should the investigator decide to reinitiate treatment with the study 
drug, the first dose intake at restart must take place at the study site to ensure at least 6-hour 
monitoring by the treating physician in a similar manner as the first intake of the study drug 
(see for guidelines for monitoring of patients taking their first dose of the study drug in
Section 5.5.5).
A reason for the interruption of treatment and dates of interruption should be documented in 
the source documents as well as in the dosage administration eCRF.
5.5.7
Recommendations on treatment of multiple sclerosis relapse
A standard course of intravenous corticosteroids (methylprednisolone) on an inpatient or 
outpatient basis is allowed for treatment of relapses as clinically warranted. Steroid treatment 
should consist of 3 to 5 days and up to 1000 mg methylprednisolone/day.
Standard-of-care procedures will be followed during treatment of relapses.
Use of any oral tapering is not permitted.
The use of steroid therapy should be recorded in the use of steroids for treatment of relapses 
eCRF. Refer to Section 6.4.3 for the instruction on conduct of the study MRI during relapse 
and steroid treatment.
Investigators should consider the added immunosuppressive effects of corticosteroid therapy 
and increase vigilance regarding infections during such treatment and in the weeks following 
administration.
Should a patient show evidence or suspicion of infection, please refer to the guidance on 
monitoring of patients with infections outlined in Appendix 3.
 


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Should a patient develop any neurological symptoms or signs, unexpected for MS in the 
opinion of the investigator or accelerated neurological deterioration, the investigator should 
immediately schedule an MRI and follow the guidance on monitoring of patients with 
symptoms or signs of neurological deterioration inconsistent with MS outlined by Appendix 3.
Steroids should not be taken before conducting the unscheduled MRI.
5.5.8
Concomitant treatment
All concomitant medications taken within 30 days before Screening (Visit 1) and during the 
study must be recorded. Both the start date and the end date for each medication should be 
captured on the prior medications/significant nondrug therapies eCRF, the previous MS 
treatment eCRF, the concomitant medications/significant nondrug therapies eCRF, and the 
steroid treatment of MS relapses eCRF.
Patients taking dimethyl fumarate, glatiramer acetate, or IFN beta before study entry may 
continue to take this medication up to the last day before randomization. These patients will 
be randomly assigned to and start study drug on the day of their next scheduled dose.
A standard short course of corticosteroids (methylprednisolone IV) is allowed for treatment of 
relapses (Section 5.5.7). Treatment with topical corticosteroids in the eyes, ears, or nose, on 
the skin or through inhalation, is also allowed, if the potential systemic absorption of the 
corticosteroid component due to that treatment can be regarded as negligible and the condition 
being treated does not warrant study discontinuation per protocol. If a course of systemic 
corticosteroid treatment is required for treatment of uveitis, this is also acceptable.
The medications allowed for the treatment of adverse reactions and relapses are not 
considered study supplies and, therefore, need to be supplied by the study site.
Medications for the symptomatic treatment of MS such as baclofen, fampridine, 
methylphenidate, or modafinil are acceptable. As far as possible, every effort should be made 
to keep the dosages stable from Screening through EOT.
The investigator should instruct the patient to notify the study site about any new medications 
that they take after the start of the study drug. All medications and significant nondrug 
therapies (including physical therapy and blood transfusions) administered after the patient 
starts treatment with study drug must be recorded on the concomitant medications/significant 
nondrug therapies eCRF and steroid therapies eCRF.
5.5.9
Prohibited treatment
Use of the following treatments is NOT allowed after randomization:

Immunosuppressive medication (e.g., cyclosporine, azathioprine, methotrexate, 
cyclophosphamide, mitoxantrone, cladribine)

Other concomitant medications: immunoglobulins, monoclonal antibodies (including 
natalizumab), IFN beta, adrenocorticotropic hormone, other disease-modifying 
medications approved for MS including those approved subsequent to the start of this 
study
The administration of any live or live-attenuated vaccine (including for measles) is prohibited 
while patients are receiving fingolimod and for 8 weeks after fingolimod discontinuation. 
 


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5.5.10
Discontinuation of study treatment and premature patient withdrawal
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason.
If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the study completion eCRF.
Patients may be withdrawn from the study for any of the following reasons:

Withdrawal of the informed consent

Lost to follow-up

Withdrawal at the investigator’s discretion
Patients who discontinue study drug should NOT be considered withdrawn from the study 
unless one of the previous reasons apply. These patients are required to follow the abbreviated 
schedule of assessment (see Table 6-2). Patients who discontinue the study drug should be 
treated according to the best standard of care. Protocol violations should not lead to patient 
withdrawal unless they indicate a significant risk to the patient’s safety.
For patients who are lost to follow-up (i.e., those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show due diligence by documenting in the source documents steps taken to contact the patient 
(e.g., dates of telephone calls, registered letters). In case of death, a patient will be considered 
withdrawn from the study.
The appropriate personnel from the site and Novartis 
 will assess whether study 
treatment should be discontinued for any patient whose treatment code has been broken 
inadvertently for any reason. Patients who discontinue study treatment should NOT be 
considered withdrawn from the study. A Study Drug Discontinuation Form should be 
completed, giving the date and primary reason for stopping study treatment. See Section 6 for 
the required assessments of these patients after discontinuation of study treatment. The 
investigator must also contact the IVRS to register the patient’s discontinuation from study 
drug. 
5.5.11
Emergency unblinding of treatment assignment for patients on 
fingolimod
Emergency unblinding should only be undertaken when it is essential to treat the patient 
safely and efficaciously. Most often, study drug discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study patient who presents with an 
emergency condition. Emergency code breaks are performed using the IVRS. When the 
investigator contacts the system to unblind a patient, he or she must provide the requested 
patient identifying information and confirm the necessity to unblind the patient. The 
investigator will then receive details of the drug treatment for the specified patient and a fax 
or e-mail confirming this information. The system will automatically inform the 
 monitor 
for the site and the clinical leader at Novartis 
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It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IVRS in case of emergency. The investigator will inform the patient how to contact 
his/her backup in cases of emergency when he or she is unavailable. The investigator will 
provide protocol number, study drug name if available, patient number, and instructions for 
contacting the local Novartis CPO (or any entity to which it has delegated responsibility for 
emergency code breaks) to the patient in case emergency unblinding is required at a time 
when the investigator and backup are unavailable.
5.5.12
Study completion and post-study treatment
The study will be considered completed for an individual patient when he or she completes 
Visit 7/EOT. 
Patients who are prematurely withdrawn from the study will not be replaced.
The investigator also must provide follow-up medical care for all patients who are 
prematurely withdrawn from the study or must refer them for appropriate ongoing care.
5.5.13
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated as described in Table 6-2 for a 
prematurely withdrawn patient. The investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator will be responsible for informing the institutional review 
boards (IRBs) or independent ethics committees (IECs) of the early termination of the trial.
6
Visit schedule and assessments
The assessment schedule listing all assessments and visits to be performed under this protocol 
is provided in Table 6-1.
Starting at Visit 3, the visit window for all study visits is ±5 days. Sites are encouraged to 
comply with this visit window as much as possible. Follow-up will occur within 3 months 
after the last dose of study drug for all patients (i.e., 3 months from the last study drug 
dose/EOT for patients who completed the study or 3 months from the last study drug dose for 
patients who were discontinued from the study). For any patients who permanently 
discontinue study drug early but decide to continue in the study, if the follow-up visit falls 
within the visit window for a scheduled visit, then assessments for both visits should be 
combined and completed. In addition to the scheduled visits, patients may have unscheduled 
visits following an onset of MS relapse or for other reasons as indicated in the protocol. All 
information should be collected per the unscheduled visit eCRF.
 


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Table 6-1
Assessment schedule
Period
Screening
Treatment Period
FUa
Visit
1
2
3
4
5
6
7/EOT
Month
Day –45 
to –1
Day 1 
Randomization
1
3
6
9
12
EOT
+3
Visit window (days)
±5
±5
±5
±5
±5
±5
Obtain informed consent
X
Background/demography
X
Inclusion/exclusion criteria
X
X
Medical history
X
MS history/MS treatment
X
Prior/concomitant medication
X
X
X
X
X
X
X
X
Pregnancy test (serum)
X
Pregnancy test (urine dipstick)
X
X
X
X
X
X
X
Physical examination
X
X
X
X
Ophthalmologic examinationb
X
X
X
X
Dermatology examination
X
X
Randomization
X
Vital signsc/body weight
X
X
X
X
X
X
X
X
Pulmonary function tests
X
X
X
X
12-lead electrocardiogram
X
Xd
X
Blood chemistry and hematology
X
X
X
X
X
X
X
Retrospective analysis blood sample
X
Serology
X
First-dose monitoring
X
Urinalysis 
X
X
X
X
X
X
X
X
Study drug dispensation
X
X
X
X
X
Study drug accountability
X
X
X
X
X
Magnetic resonance imaging
X
X
EDSS
X
X
X
MS relapseg
X
X
X
X
X
X
X
X
TSQM
X
X
X
C-SSRS
X
X
X
X
X
X
X
Adverse events/SAEs
X
X
X
X
X
X
X
X
Study completion form
X
Abbreviations: C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; EDSS=expanded 
disability status scale; EOT=end of treatment; FU=follow-up; HSV=herpes simplex virus; MS=multiple sclerosis; 
 
; SAE=serious adverse event; 
; 
TSQM=treatment satisfaction questionnaire for medication.
a. Follow-up will occur 3 months (12 weeks) after the last dose of study drug for all patients.
b. The ophthalmology examination will include eye history, visual acuity, dilated ophthalmoscopy, and any 
procedures necessary to assess macular edema. Optical coherence tomography and fluorescein angiography will 
be done only if needed to confirm macular edema.
c. Body temperature is collected only at Screening, Visit 7/EOT, and at the follow-up visit.
d. A 12-lead ECG will be performed before fingolimod and glatiramer acetate administration, and 6 hours after the 
fingolimod administration only. 
 


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e. Patients will be tested for human immunodeficiency virus, varicella zoster virus (as per guidance in
Appendix 3), HSV-1, HSV-2, and rubeola virus.
 
 
g. Patients should report symptoms indicative of a relapse at a scheduled visit or at any other time and will be 
instructed to immediately contact the treating physician if they develop new or reoccurring or worsening 
neurological symptoms. A neurological examination by the independent evaluating physician must be arranged as 
soon as possible, preferably within 7 days of the onset of symptoms.
Table 6-2
Abbreviated schedule of assessments for patients who discontinue 
study drug
Period
Off-Treatment
Visit
5
6
7/EOS
Month
6
9
12
Visit window (days)
±5
±5
±5
MS relapsesa
X
X
X
MS treatment/steroids
X
X
X
Concomitant medications
X
X
X
Magnetic Resonance Imaging
EDSS
X
TSQM
X
C-SSRS
X
X
X
Physical exam
X
X
Ophthalmologic examc
X
Dermatology examination
X
Vital signsd/body weight
X
X
X
Pulmonary function tests
X
Laboratory values
Xe
Xe
X
Adverse events
X
X
X
SAE reporting
X
X
X
Abbreviations: C-SSRS=Columbia-Suicide Severity Rating Scale; EDSS=expanded disability status scale; 
EOS=end of study; MS=multiple sclerosis;
 
; SAE=serious adverse event; 
; TSQM=treatment satisfaction questionnaire for medication.
a. Patients should report symptoms indicative of a relapse at a scheduled visit or at any other time and will be 
instructed to immediately contact the treating physician if they develop new or reoccurring or worsening 
neurological symptoms. A neurological examination by the independent evaluating physician must be arranged 
as soon as possible, preferably within 7 days of the onset of symptoms.
c. The ophthalmology examination will include eye history, visual acuity, dilated ophthalmoscopy, and any 
 


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procedures necessary to assess macular edema. Optical coherence tomography and fluorescein angiography 
will be done only if needed to confirm macular edema.
d. Body temperature is collected only at Visit 7/EOS.
e. Urinalysis only.
6.1
Information to be collected on screening failures
Those patients who have signed informed consent and fail to meet all inclusion/exclusion 
criteria will not be randomized and will be deemed screening failures. A reason will be 
documented on the screening log eCRF.
6.2
Patient demographics/other baseline characteristics
Demographic data will be collected and recorded in the demography eCRF including date of 
birth, sex, and race. Multiple sclerosis history and previous MS treatment will be recorded in 
the MS history and previous MS treatment eCRF pages, respectively. The majority of 
evaluations (Table 6-1) will be performed at Screening. Only review of inclusion/exclusion 
criteria, vital signs, ECG, and urine pregnancy test (if applicable) will be repeated at Day 1, 
(randomization). The baseline laboratory values should be available before randomization 
(part of assessment of inclusion/exclusion criteria). 
The treating physician will ask about relevant diseases of the following organs and organ 
systems: skin; eyes, ears, nose, throat, head and neck (including the thyroid); lungs; heart; 
breasts; abdomen; lymph nodes; musculoskeletal (including extremities and spine); 
genitourinary, gynecological organs; and rectum. History of allergies, in particular with 
respect to Gd-diethylenetriamine penta-acetic acid (Gd-DTPA) will be queried. Patients will 
be asked if they have a history of alcohol or drug abuse or a history of psychiatric disorders. 
Any previous disease or surgeries will also be documented. Medical history should be 
supplemented by review of the patient’s medical chart and/or by documented dialog with the 
patient’s treating physician. The source of information will be recorded in the relevant 
medical history/current medical conditions eCRF.
Previous MS history (including history of relapses) needs to be documented in the patient’s 
medical chart and/or in documented dialog with the patient’s treating physician.
Information relating to MS history will be collected in the study including: date of MS 
diagnosis, date of MS symptoms, eye history (e.g., optic neuritis or uveitis), MS relapse 
history (i.e., number of relapses since first MS symptoms and number of relapses that required 
steroid treatment), and history of medications used to treat MS. These data will be collected 
and recorded in the MS medical history, ophthalmology screening, and MS treatment eCRFs. 
Medications used to treat MS may include glatiramer acetate, IM IFN beta-1a, SC IFN 
beta-1a, IFN beta-1b, natalizumab, azathioprine, methotrexate, or any other medications used 
as MS treatments.
During the study medications to treat MS-related symptoms should be recorded in the 
concomitant medication eCRF. Multiple sclerosis history should be supplemented by review 
of the patient’s medical chart and/or by documented dialog with the patient’s primary treating 
physician.
 


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In patients with diabetes, diabetes-specific medical history to be collected and recorded in the 
eCRF will include type 1 vs. type 2, date of diabetes diagnosis, antidiabetic therapy, and 
presence of diabetes-related complications.
6.3
Treatment exposure and compliance
In order to collect accurate information about the study drug exposure, the following records 
should be maintained for each randomly assigned patient: records of study drug dispensed and 
returned, dosages administered (in blinded fashion) and intervals between visits. These data 
should be transcribed on the dosage administration record eCRF.
Compliance will be assessed by the investigator and/or study personnel at each visit using 
capsule and syringe counts and information provided by the patient. A monitor will perform 
and document drug accountability during site visits and at the end of the study.
6.4
Efficacy
6.4.1
Multiple sclerosis relapse
Patients should be instructed to report symptoms indicative of an MS relapse at any time, 
regardless of whether a visit is scheduled. A patient must be instructed to immediately contact 
the study site if a new, reoccurring, or worsening neurological symptom develops.

General definition of relapse: appearance of a new neurological abnormality or 
worsening of previously stable or improving preexisting neurological abnormality, 
separated by at least 30 days from onset of a preceding clinical demyelinating event. The 
abnormality must be present for at least 24 hours and occur in the absence of fever 
(<37.5°C) or infection.

Definition of confirmed relapse: a relapse must be confirmed by the independent 
evaluating physician (neurologist). It is recommended that this occur as soon as possible 
but no more than 7 days from the onset of symptoms. A relapse is confirmed when it is 
accompanied by an increase of at least half a step (0.5) on the EDSS or an increase of 
1 point on 2 different functional systems (FSs) of the EDSS or 2 points on 1 of the FS 
(excluding bowel and bladder and cerebral FSs). 
Reporting of relapse
In order to maintain rater-blinding, a special coordination between the treating physician and 
the independent evaluating physician (blinded rater) must be followed for relapse assessment. 
A patient may report symptoms indicative of a relapse at a scheduled visit or at any other time. 
Patients will be instructed to immediately contact the treating physician if they develop new 
or reoccurring or worsening neurological symptoms.
Upon reporting symptoms indicative of a relapse, the treating physician will assess whether 
the symptoms had onset in the presence of fever or infection. If fever or infection can be 
excluded, a neurological examination by the independent evaluating physician must be 
arranged as soon as possible, preferably within 7 days of the onset of symptoms. If fever or 
infection cannot be excluded, the neurological examination will be postponed until the fever 
or the infection has ceased (provided that the symptoms indicative of a relapse are still 
 


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present). Treatment with steroids should not begin before the assessment by the independent 
evaluating physician.
Based on results of the neurological examination (change in FS and EDSS scores) provided 
by the independent evaluating physician, the treating physician will record if the relapse meets 
the criteria for “confirmed relapse” as per protocol 
. All 
relapses, whether confirmed or unconfirmed, 
 should be 
recorded on the summary of MS relapses eCRF.
6.4.2
Expanded Disability Status Scale
The EDSS is a scale for assessing neurologic impairment in MS and will be used to confirm 
an MS relapse. It is a 2-part system including: (1) a series of scores in each of the 8 FSs and 
(2) steps ranging from 0 (normal) to 10 (death due to MS). The FSs are Visual, Brain Stem, 
Pyramidal, Cerebellar, Sensory, Bowel and Bladder, Cerebral, and other functions. Fatigue is 
not to be considered in determining the Cerebral Functional score.
The EDSS will be derived based on the neurological examination performed by the 
independent evaluating physician, a neurologist with experience with MS patients. Other 
qualified individuals (e.g., registered nurse or nurse practitioner) with documented experience 
in MS clinical trials might be considered for the role of EDSS rater if approved by Novartis’ 
Medical Advisor. At site initiation, the EDSS rater must have received level “C” Neurostatus 
certification within the previous year unless the EDSS rater regularly performs the assessment, 
in which case the certification can be up to 2 years old. All EDSS raters must be recertified 
every 2 years. It is recommended that a backup EDSS rater be available at each site. The 
EDSS assessments will be done as detailed in Table 6-1 or Table 6-2 for patients that 
discontinued study drug or as needed during relapse assessments.
6.4.3
Magnetic Resonance Imaging (MRI)
All MRIs will be performed at the visits as indicated in Table 6-1 or Table 6-2 for patients 
that discontinued study drug. 
The treating physician will be able to review all MRIs during the study. For analysis purposes, 
the scheduled MRIs will be reviewed and measures recorded by a blinded central MRI reader.
 


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Restrictions for magnetic resonance imaging schedule
To avoid potential interference caused by steroids used for the treatment of MS relapses, the 
following restrictions apply for this study:

In case of relapse, if an MRI is scheduled within 30 days of the initiation of steroid 
treatment, this MRI should be performed before steroid treatment is initiated

No MRI scan should be performed while a patient is on steroid therapy or within 30 days 
after termination of steroid therapy
Scanning T1-weighted image before and after administration of contrast medium 
(0.1 mmol/kg Gd-DTPA) as well as T2-weighted (T2 and proton density) images will be 
performed.
The contrast agent may occasionally cause nausea and vomiting. Allergic reactions may also 
occur very rarely and, in extremely rare instances, can be potentially serious and require 
immediate anti-anaphylactic treatment (IV epinephrine, dopamine, steroids, etc.). The patients 
known to be allergic to Gd may participate in the trial with MRI assessment modified to forgo 
contrasted MRI images.
Before the start of the study, a radiologist and technician from each center will receive an 
MRI manual outlining technical implementation, image quality requirements, and MRI 
administrative procedures. Each site will be asked to program the MRI scanner that is 
designated for evaluation of the study patients and perform and submit a “dummy scan” or 
“dry run” to assess the image quality and to evaluate the compatibility of the electronic data 
carrier. Once the dummy scan has been approved by the central MRI reader, all parameter 
settings for the study-specific MRI sequences must remain unchanged for the duration of the 
study.
Data handling and evaluation
The quality of each scan performed will be assessed by the blinded MRI reader. As soon as 
the scan is received by the central MRI reading center, it will be evaluated for quality, 
completeness, and adherence to the protocol. Confirmation of MRI quality or a description of 
the quality problems, if detected, will be communicated to the site. If the scan is incomplete or 
incorrectly performed, the study center will be asked to repeat it as soon as possible. After 
completion of the quality check, all scans will be analyzed according to the MRI protocol.
 


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6.5
Safety Assessments
Safety assessments include the following:

Physical and neurological examination

Vital sign measurements

Laboratory evaluations

ECG results

Ophthalmologic examinations

Pulmonary function tests (PFTs)

Dermatological examination

C-SSRS
6.5.1
Physical examination
A complete physical examination will be performed at visits as described in Table 6-1 or 
Table 6-2 for patients that discontinued study drug and will include an assessment of skin, 
head and neck, lymph nodes, heart, lungs, abdomen, and back, and comments on general 
appearance. Initial neurological examination (with fundoscopic examination) will be a part of 
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should ask the patient if they have any new or changed skin lesions as part of each physical 
examination. If skin lesions (suspected to be precancerous or cancerous) are identified during 
the physical examination, the patients should be referred to a dermatologist. (Also refer to 
Section 6.5.10 for dermatological examination).
All significant findings that are present at Screening must be reported on the relevant medical 
history/current medical conditions eCRF. Significant findings made after randomization that 
meet the definition of an AE must be recorded on the AEs eCRF.
Patients who experience new significant cardiac symptoms (e.g., congestive heart failure, new 
murmur, ischemic heart disease) or symptoms consistent with pulmonary hypertension 
(e.g., exertional dyspnea, chest pain, and syncope), should be referred to a specialist 
(e.g., cardiologist) for further diagnostic workup (e.g., echocardiography) and appropriate 
management as close as possible to the time of the onset of symptoms.
6.5.2
Vital signs
Vital signs will be collected as described in Table 6-1. These will include supine and standing 
heart rate and systolic and diastolic blood pressures. After the patient has been supine for 
5 minutes, systolic and diastolic blood pressure will be measured 3 times using an automated 
validated device (e.g., OMRON) with an appropriately sized cuff. The repeat measurements 
will be made at 1- to 2-minute intervals, and the mean of the 3 measurements will be used. In 
case the cuff sizes available are not large enough for the patient's arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used. Heart rate and blood 
pressure will then be measured in the same manner with the patient in the standing position. A 
sudden, significant fall in blood pressure (>20 mm Hg systolic or >10 mm Hg diastolic) 
between 2 and 5 minutes after standing from the supine position will be defined as orthostatic 
hypotension.
Body weight will be measured as described in Table 6-1. Body temperature will be measured 
only at Screening, Visit 7/EOT, and at follow-up. 
Clinically notable vital signs are defined in Appendix 1.
6.5.3
Laboratory evaluations
Routine blood samples will be collected as described in Table 6-1 and Table 6-2 and analyzed 
by the central laboratory. Blood samples taken at the screening visit are to be in the fasting 
state. Blood samples taken at subsequent visits are recommended to be in the fasting state. 
Details regarding collection of samples, shipment of samples, reporting of results, laboratory 
reference ranges, and alerting abnormal values will be supplied to the site before site initiation 
in a study laboratory manual. The results of the analysis will be made available to each site by 
the central laboratory, at the earliest, 48 hours after receipt of the samples by the central 
laboratory.
Investigators will be asked to comment on those abnormalities on the respective laboratory 
result page, including a notation of the clinical significance of each abnormal finding in the 
patient’s source documents. The laboratory sheets will be filed with the patient’s source 
documents. Abnormal laboratory values should not be recorded on the AE eCRF; however, 
 


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any diagnoses (or signs or symptoms if a diagnosis is not possible) associated with the 
abnormal findings should be recorded on the AE eCRF.
Clinically notable laboratory findings are defined in Appendix 1.
6.5.3.1
Hematology
Hematology parameter blood samples will be collected as described in Table 6-1 and will 
include: red blood cell count, total and differential WBC count (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils), platelet count, hemoglobin, hematocrit, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, and red blood cell morphology. In a subset of patients CD4+, CD8+, Th17, Treg,
and other T-lymphocyte subsets will be determined.
For study blinding purposes (of fingolimod arms) only the absolute counts for eosinophils, 
basophils, and monocytes will be communicated to sites by the central laboratory. The 
absolute total WBC, neutrophil, and lymphocyte counts will be measured at each visit by the 
central laboratory and will be blinded from the sponsor and the Investigator and will only be 
communicated to the site in case of a notable abnormality as defined in Appendix 1 and as per 
guidance in Appendix 3.
6.5.3.2
Clinical chemistry and blood serology
Blood samples will be collected as described in Table 6-1 and will include the following 
parameters: sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate, blood 
urea nitrogen, uric acid, random glucose, albumin, AP, creatinine, ALT, AST, GGT, amylase, 
total bilirubin, conjugated bilirubin, HbA1c, total cholesterol, triglycerides, high-density 
lipoprotein, and low-density lipoprotein. Abnormal laboratory parameters inconsistent with 
clinical presentation of MS or suspicious of underlying medical condition should be repeated
for accuracy.
If an increase of amylase above the clinically notable value (≥300 U/L) is observed at any 
postrandomization visit, lipase should be tested to determine the origin of elevated amylase 
(pancreatic versus extra-pancreatic).
Serology testing will also be performed in all patients at Screening to determine the patient's 
immune status with respect to the following viruses:

Herpes simplex virus-1 (HSV-1)

Herpes simplex virus-2 (HSV-2)

Rubeola (Measles)

Human immunodeficiency antibodies
Patients without acceptable evidence of immunity against VZV (per Appendix 3) at Screening 
will be excluded from the study. Patients testing positive for HIV are excluded from the study.
Patients who are negative for HSV-1 immunoglobulin G (IgG), HSV-2 IgG or rubeola IgG 
antibodies should be informed of their status and be instructed to promptly report any 
exposure to these viruses e.g., to a person with cold sores, herpes genitalis, or measles, 
respectively. In case of exposure, early treatment with appropriate antiviral drugs and/or 
immunoglobulin should be considered in consultation with a local infectious disease expert.
 


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A positive IgG antibody result does not indicate active infection per se, but only evidence of 
prior exposure to viral antigens through past infection or vaccination. Patients with prior 
infection may be at risk of viral reactivation (e.g., cold sores, genital ulcers or shingles) and 
should be instructed to inform the investigator of any signs or symptoms suggestive of these 
conditions, so that prompt treatment may be initiated. 
If a patient experiences symptoms of a new ischemic or thrombotic AE, the following 
additional laboratory 
assessments should be performed: prothrombin time/partial 
thromboplastin time, homocysteine, activated protein C, lupus anticoagulant, antiphospholipid 
antibody, protein C, protein S, fibrinogen, and antithrombin III.
A serum pregnancy test will be conducted at Screening on all females, regardless of 
child-bearing potential.
 
 
6.5.3.3
Urinalysis
Urinalysis will be performed as indicated in Table 6-1 and Table 6-2. The following 
parameters will be analyzed: leukocytes, specific gravity, bilirubin, blood, glucose, ketones, 
pH, protein, and urobilinogen. 
If a patient experiences edema or significant weight gain (Appendix 1), urinalysis by dipstick 
for proteinuria will be performed. If dipstick urinalysis detects proteinuria, urinalysis should 
be repeated. If proteinuria is confirmed upon repeat testing, the protein/creatinine ratio should 
be determined in a spot urine sample. In case of abnormal spot urine protein/creatinine ratio, 
the patient should be referred to a nephrologist for further evaluation and assessments, 
including possible 24-hour urine collection.
6.5.4
Electrocardiogram
Standard 12-lead ECGs will be collected as described in Table 6-1. Digital ECG devices will 
be provided to each clinical site by the central ECG reader for the duration of the study. The 
screening ECG report from the central reader must be available to confirm patient eligibility 
before randomization. A 12-lead ECG will be performed at Visit 2 before study drug 
administration for patients receiving fingolimod and patients receiving glatiramer acetate and 
6 hours after the study drug administration, for patients receiving fingolimod only. 
See Section 5.5.5 for guidelines for monitoring patients taking their first dose of fingolimod 
who had a prolonged QTc interval (>450 msec males, >470 msec females) before dosing or 
during a 6-hour observation period, or at additional risk for QT prolongation (e.g., 
hypokalemia, hypomagnesemia, congenital long-QT syndrome), or on concurrent therapy 
with QT-prolonging drugs with a known risk of torsades de pointes.
Detailed instructions describing the process for recording and transmission of the ECGs will 
be outlined in the study-specific manual and provided to the site before the start of the study. 
Paper ECGs will be printed, photocopied to preserve the ink if necessary, and kept at the site 
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Interpretation of the tracing must be made by a qualified physician. Each ECG tracing should 
be labeled with the study number, patient initials, patient number, date, and kept in the source 
documents at the study site. Only clinically significant abnormalities should be reported as 
medical history/current medical conditions or AEs on the eCRF. Clinically significant 
findings must be discussed with the Medical Monitor before enrolling the patient in the study.
6.5.5
Ophthalmologic examinations and optical coherence tomography
An ophthalmic examination will be performed to screen for macular edema as described in 
Table 6-1 and Table 6-2 for patients that discontinued study drug. An optical coherence 
tomography (OCT) and fluorescein angiography (FA) will be done only if needed to confirm 
macular edema. If there is a suspicion of macular edema at Screening, an OCT and FA should 
be performed to confirm the diagnosis. If the diagnosis is confirmed, the patient should be 
deemed a screening failure and should not be randomly assigned.
Patients with a history of or newly diagnosed uveitis after initiation of study drug may require 
more frequent ophthalmic evaluations. Refer to the Guidance for Ophthalmic Monitoring 
(Appendix 4) for details on monitoring of patients with uveitis during the study. 
Study drug must be discontinued in any patient who has a diagnosis of macular edema 
confirmed by OCT and FA.
Patients with a diagnosis of macular edema must be followed up monthly and more frequently 
if needed based on the ophthalmologist’s judgment. Further ophthalmologic evaluations will 
be conducted until such time as resolution is confirmed or no further improvement is expected 
by the ophthalmologist (based on a follow-up period of not less than 3 months). If the patient 
does not show definite signs of improvement on examination by specialized testing (e.g., 
OCT) 6 to 8 weeks after discontinuation of study drug, then therapy for macular edema in 
conjunction with an ophthalmologist experienced in the management of this condition should 
be initiated.
6.5.6
Pregnancy and assessments of fertility
Serum pregnancy test will be performed for all women by the central laboratory as detailed in 
Table 6-1. Patients becoming pregnant will be recommended to interrupt the study drug. 
Additional pregnancy testing may be performed at the investigator’s discretion during the 
study. 
 


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6.5.8
Chest x-ray
This section is no longer applicable after the changes made at protocol amendment 2.
6.5.9
Pulmonary function tests
Pulmonary function tests evaluating FEV1, FVC, and DLCO will be performed at Screening, 
Month 6, Month 12, End of Study, and 3 months after study drug discontinuation as indicated 
in Table 6-1 and Table 6-2. This test will be conducted in all patients who are enrolled into 
the study and in the manner consistent with the standard pulmonary laboratory practice. 
Any condition that might affect the outcome of PFTs including infection, respiratory 
symptoms, occupational exposures (including asbestos), and cigarette smoking, needs to be 
collected before every PFT testing and transcribed to the PFT eCRF page. 
Patients who discontinue study drug due to respiratory AE(s) should be evaluated by a 
pulmonary specialist and further investigations (e.g., PFTs, chest x-ray or HRCT, biopsy) 
should be performed as needed. 
Spirometry
The technician should demonstrate the appropriate technique to the patient and follow the 
standard procedure. The quality of the tests must be accounted for including the technicians’ 
comments (especially when, despite proper coaching of the patient, full collaboration cannot 
be achieved). The FEV1/FVC ratio will be calculated centrally by the trial statistician.
A minimum of 3 acceptable maneuvers will be performed at each visit. The acceptability 
criteria are a satisfactory start of test and a satisfactory end of test. In addition, the technician 
should observe that the patient understood the instructions and performed the maneuver with a 
maximum inspiration, a good start, a smooth continuous exhalation, and maximal effort. The 
largest FVC and the largest FEV1 will be recorded, after examining the data from all of the 
acceptable curves, even if the 2 values do not come from the same curve. Please refer to the 
American Thoracic Society/European Respiratory Society guidelines for standardization of 
spirometry (Miller et al, 2005a; Miller et al, 2005b) and single breath determination of carbon 
monoxide uptake in the lung (MacIntyre et al, 2005).
If for any reason a patient is permanently discontinued from study medication the patient will 
have PFTs performed at his last visit or within 30 days of the study drug discontinuation. 
Refer to Appendix 3 for Guidance on monitoring patients with pulmonary function safety 
concern.
Forced expiratory volume in 1 second (FEV1):
The FEV1 describes the volume (in Liters) that is expelled within one second of forced 
expiration after a maximal inspiration and reflects the large airway resistance. A decrease in 
FEV1 serves as a good parameter for detection of an obstructive ventilatory defect.
Forced vital capacity (FVC):
The FVC denotes the volume of gas (in Liters) which is exhaled during a forced expiration 
starting from a position of full inspiration and ending at complete expiration. This parameter 
 


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is normal or might be slightly decreased in obstructive disease but shows a mild to severe 
decrease in restrictive disease.
Diffusion capacity of carbon monoxide (DLCO):
Gas exchange is assessed by the DLCO evaluated by the single breath holding method. It is a 
measurement of carbon monoxide (CO) transfer from the lung to pulmonary capillary blood 
over a breath-holding period. Due to ability of CO to bind to hemoglobin, the diffusion 
capacity needs to be corrected for hemoglobin to reflect an altered lung gas transport rather 
than altered hemoglobin.
The average of at least 2 acceptable tests that meet the repeatability requirement of either 
being with 3 mL CO/min/mm Hg (or 1 mmol/min/kPa) of each other or being within 10% of 
the highest value should be reported.
A DLCO test is acceptable if it fulfills all the following criteria:

Use of proper quality-controlled equipment 

Inspired volume of greater than 85% of largest vital capacity in less than 4 seconds

A stable calculated breath hold for 10 (±2) seconds. There should be no evidence of leaks 
or Valsalva or Mueller maneuvers

Expiration in less than 4 seconds (and sample collection time less than 3 seconds), with 
appropriate clearance of dead space and proper sampling/analysis of alveolar gas
All values must be corrected for hemoglobin concentration in the study. 
The DLCO is usually expressed in European CI conventional units: mL CO/min/torr (or 
mL CO/min/mm Hg), whereas the US mainly uses SI units: mmol CO/min/kPa (Conversion 
factor: SI units × 2.986 = CI units).
6.5.10
Dermatological examination
A dermatologist will complete a dermatological examination as outlined in Table 6-1 and 
Table 6-2 to support monitoring of patients for the potential development of new skin cancers 
during the study. For patients who discontinue treatment early, a dermatological examination 
should be performed at end of study. Study drug should be discontinued in patients who 
develop a new skin cancer during the study. 
6.5.11
Columbia-Suicide Severity Rating Scale
The C-SSRS, is a semi-structured interview designed to systematically assess and track 
suicidal AEs (behavior and ideation) throughout different settings including clinical studies. 
The C-SSRS captures the occurrence, severity, and frequency of suicide-related thoughts and 
behaviors. The C-SSRS will be administered by an IVRS with the patient entering responses 
directly into the IVRS. Caregivers will not be allowed to answer the C-SSRS questions on 
behalf of the patient. Sites must review reports received from the system for any answers 
indicative of suicidal ideation and AEs. Adverse events ascertained through the administration 
of the C-SSRS will be documented. This scale was developed by researchers at Columbia 
University and will be administered in this study as specified in the assessment schedules 
 


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(Table 6-1 and Table 6-2). In case the score is 4 or above, the patient must be referred to the 
health care professional for further assessment and/or treatment.
6.5.12
Appropriateness of safety measurements
The safety assessments selected are standard for this indication and patient population. 
Ophthalmic evaluation has been included for detection of macular edema. Macular edema is 
an AE of special interest in patients treated with fingolimod because of the higher incidence 
seen in treated patients compared with active and placebo control groups in previous studies.
6.6
Other assessments
6.6.1
Health-related quality of life
Patients must complete the TSQM, 
 questionnaires before other 
clinical assessments at any given visit. Completed questionnaires will be reviewed and 
examined by the investigator before the clinical examination for responses that may indicate 
potential 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 the occurrence of AEs or SAEs is confirmed, the physician must record the events. 
Investigators should not encourage the patients to change the responses reported in the 
questionnaires.
6.6.1.1
Treatment Satisfaction Questionnaire for Medication v1.4 (TSQM v1.4)
Treatment Satisfaction Questionnaire for Medication (TSQM) was developed and validated as 
a general measure for treatment satisfaction (Atkinson 2004). The TSQM version 1.4 contains 
14 items assessing the following 4 domains: Global Satisfaction, Effectiveness, Side Effects, 
and Convenience. This PRO must be completed prior to any other study visits assessments at 
the baseline, 6 and 12 month visits.
 


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6.6.2
Resource utilization
Not applicable.
6.6.3
Pharmacogenetics/pharmacogenomics
Not applicable.
 


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7
Safety monitoring
7.1
Adverse events
An AE is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be 
related to study drug. Study drug includes the investigational drug under evaluation and the 
comparator drug that is given during any phase of the study. Medical conditions and diseases 
present before starting study drug are only considered AEs if they worsen after starting study 
drug. Abnormal laboratory values or test results constitute AEs only if they induce clinical 
signs or symptoms, are considered clinically significant, or require therapy.
The occurrence of AEs should be sought by nondirective questioning of the patient at each 
visit during the study. Adverse events also may be detected when they are volunteered by the 
patient during or between visits or through physical examination, laboratory test, or other 
assessments. All AEs must be recorded in the AEs eCRF with the following information:
1. the severity grade (mild, moderate, or severe)
2. its relationship to the study drug(s) (suspected/not suspected)
3. its duration (start and end dates or if continuing at final examination)
4. whether it constitutes a serious AE (SAE)
An SAE is defined as an event which:

is fatal or life threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or preplanned treatment for a preexisting condition that is unrelated to the 
indication under study and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes previously listed
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements (Section 7.2).
All AEs should be treated appropriately. Treatment may include one or more of the following: 
no action taken (i.e., further observation only); study drug dose adjusted/temporarily 
 


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interrupted; study drug permanently discontinued due to this AE; concomitant medication 
given; nondrug therapy given; or patient hospitalized/patient’s hospitalization prolonged. The 
action taken to treat the AE should be recorded on the AE CRF. 
For patients who experience an ischemic or thrombotic AE, specialist advice should be sought 
to determine diagnostic and therapeutic procedures. If a laboratory screen for coagulation 
abnormalities is deemed appropriate, it should include the following additional assessments: 
prothrombin time/partial thromboplastin time, homocysteine, activated protein C, lupus 
anticoagulant, 
antiphospholipid 
antibody, 
protein 
C, 
protein 
S, 
fibrinogen, 
and 
antithrombin III.
Patients who discontinue due to respiratory AEs should be evaluated by a pulmonary 
specialist and additional investigations (e.g., PFTs, chest x-ray or HRCT, biopsy) should be 
performed as needed.
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome. Sites should send all unscheduled laboratory samples to 
the central laboratory to ensure that the laboratory data are included in the clinical database 
and reported.
Information about common side effects already known about the investigational drug can be 
found in the investigator brochure or will be communicated between investigator brochure 
updates in the form of investigator notifications. This information will be included in the 
patient informed consent and should be discussed with the patient during the study as needed.
7.2
Serious adverse event reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 30 days after the patient has stopped study 
participation (defined as time of last dose of study drug taken or last visit whichever is later), 
must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 30-day period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess the relationship of any SAE to study drug, complete the 
Serious Adverse Event Report Form in English, and send the completed, signed form by fax 
within 24 hours to the local Novartis Drug Safety and Epidemiology Department. The 
telephone and telecopy number of the contact persons in the local Clinical Safety and 
Epidemiology Department, specific to the site, are listed in the investigator folder provided to 
each site. The original copy of the SAE Report Form and the fax confirmation sheet must be 
kept with the CRF documentation at the study site.
 


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Follow-up information is sent to the same person to whom the original Serious Adverse Event 
Report Form was sent, using a new Serious Adverse Event Report Form stating that this is a 
follow-up to the previously reported SAE and giving the date of the original report. The 
follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, whether the blind was broken or not, and whether the patient continued or 
withdrew from study participation.
If the SAE is not previously documented in the investigator’s brochure or package insert (new 
occurrence) and is thought to be related to the Novartis study drug, a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an investigator 
notification to inform all investigators involved in any study with the same drug that this SAE 
has been reported. Suspected unexpected serious adverse reactions will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with 
Directive 2001/20/EC or as per national regulatory requirements in participating countries.
7.2.1
Serious adverse event notification: multiple sclerosis relapse
Any MS relapses, as a general rule, should be reported on the relapse CRF instead of the 
AE/SAE forms. However, if, in the judgment of the investigator, any MS relapse is unusually 
severe and warrants specific notification, then an SAE Report Form must be completed and 
submitted according to SAE reporting procedures outlined above.
7.3
Pregnancies
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
7.4
Data safety monitoring board
An FTY720 data safety monitoring board (DSMB) has been established with a primary goal 
to monitor the safety of patients participating in all FTY720 studies, including the present 
study. The DSMB is an external board comprising specialists with specific knowledge of MS 
and other areas related to the safety of FTY720. Specific AEs of interest from this study will 
be submitted for review and evaluation by the DSMB.
 


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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 (i.e., CRO monitor or clinical team manager) will review the protocol and 
(e)CRFs with the investigators and their staff. During the study, the field monitor will visit the 
site regularly to check the completeness of patient records, the accuracy of entries on the 
(e)CRFs, the adherence to the protocol and to Good Clinical Practice, the progress of 
enrollment, and to ensure that study drug is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, MRI films, and the results of any other tests or 
assessments. All information on (e)CRFs must be traceable to these source documents in the 
patient’s file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the field monitor access to all relevant source documents to 
confirm their consistency with the (e)CRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the (e)CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the eCRF using 
fully validated software that conforms to 21 CFR Part 11 requirements. Designated 
investigator site staff will not be given access to the electronic data capture system until they 
have been trained. Automatic validation programs check for data discrepancies and, by 
generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The investigator must certify 
that the data entered into the eCRF are complete and accurate. After database lock, the 
investigator will receive a CD-ROM of the patient data for archiving at the investigational site.
8.3
Database management and quality control
Novartis or designated CRO working on behalf of Novartis review the data entered into the 
eCRFs by investigational staff for completeness and accuracy and instructs the site personnel 
to make any required corrections or additions. Queries are sent to the investigational site using 
an electronic data query. Designated investigator site staff is required to respond to the query 
and confirm or correct the data.
Concomitant medication entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
 


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Medical history/current medical conditions and AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology.
Laboratory samples, ECG readings, MRI readings, 
 will be processed centrally 
and the results will be sent electronically to a designated CRO.
Randomization codes and data about all study drug dispensed to the patient and all IVRS 
recorded dosage changes will be tracked using an IVRS. The system will be supplied by a 
vendor, who will also manage the database. The database will be sent electronically to 
Novartis (or a designated CRO).
Each occurrence of a code break via IVRS will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
9
Data analysis
9.1
Analysis sets
The following analysis sets will be used: 

Randomized set: consists of all patients who are assigned randomization numbers. The 
patients in this set are called randomized patients. This set will be used to summarize 
patient disposition, demographic and baseline characteristics, and protocol deviation 
information.

Full-analysis set (FAS): Consists of all patients who are randomly assigned and take at 
least 1 dose of study drug. Following the intent-to-treat principle, patients will be grouped 
according to the assigned treatment at randomization. Efficacy analyses will be performed 
on the FAS unless otherwise notified.

Per-protocol set: Consists of all patients in the FAS who do not have any major protocol 
deviations that could confound the interpretation of analyses conducted on the FAS. Major 
protocol deviations will be determined according to the predefined protocol deviation 
criteria before treatment unblinding. Any efficacy data after study drug discontinuation 
will be excluded. The per-protocol set will only be used for the supportive analyses of the 
primary efficacy variable.

Safety set: Consists of all patients in the FAS who take at least 1 dose of study drug. 
Patients will be analyzed according to the treatment they have actually taken. Safety and 
tolerability analyses will be performed on the safety set unless otherwise notified.

Follow-up set: The follow-up set consists of all patients in the safety set who have follow-
up visit data or who have at least 1 safety assessment (AEs, laboratory test, vital sign 
measurement, or ophthalmology assessments) 46 days or more than 46 days after study 
drug discontinuation. Patients will be grouped in the same way as previously described for 
the analysis on the safety set. Only the safety follow-up data analysis will be performed on 
the follow-up set.
 


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9.2
Patient demographics and other baseline characteristics
Demographics and background information will be summarized using frequency distributions 
for categorical variables and descriptive statistics of mean, SD, minimum, median, and 
maximum for continuous variables. Background information includes prior MS treatment, 
relevant medical history/current medical conditions, duration of the disease, the number of 
relapses experienced in the last 2 years before study enrollment, baseline MRI assessments, 
and baseline EDSS.
9.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Duration (days) of exposure to study drug will be summarized by treatment group. Frequency 
distributions will be used to summarize patient disposition and reasons for discontinuation of 
study drug. Patients who prematurely discontinue the study drug will be listed along with the 
reason for discontinuation.
The cumulative corticosteroid dose used after the start of study drug for the treatment of MS 
relapses will be summarized by treatment group in dose equivalent to methylprednisolone (the 
conversion factors will be detailed in the statistical analysis plan). The cumulative duration of 
the corticosteroid use will be summarized similarly.
9.4
Analysis of the primary variable
The primary analysis will be based on the FAS.
9.4.1
Variable
The primary outcome is the ARR which is defined as the average number of confirmed 
relapses per year (i.e., the total number of confirmed relapses divided by the total days in the 
study multiplied by 365.25). For the primary analysis, the number of relapses will include all 
the confirmed relapses experienced during the study. The time spent in the study will 
correspond to the observation period for all the relapses from first dose on study drug to end 
of study.
9.4.2
Statistical model, hypothesis, and method of analysis
The two doses of fingolimod will be tested hierarchically versus glatiramer acetate in a 
step-down procedure. For each of the two fingolimod doses, the null hypothesis is that there is 
no difference in the ARRs between patients treated with fingolimod and those treated with 
glatiramer acetate versus the alternative hypothesis that there is a difference between the 
two treatment groups. In order to preserve the Type I experiment-wise error rate, the null 
hypothesis will be rejected if the observed p value for the between-treatment comparison is 
less than the significance level as specified in the multiplicity adjustment procedure described 
later in this section. 
H01: µ FTY 0.5 mg=µ glatiramer acetate versus HA1: µ FTY 0.5 mg≠µ glatiramer acetate
H02: µ FTY 0.25 mg=µ glatiramer acetate versus HA2: µ FTY 0.25 mg≠µ glatiramer acetate
 


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No formal hypothesis will be tested between the 2 fingolimod doses because the study is not 
powered to detect a difference in treatment effect between these doses.
The hypotheses will be tested using a negative binomial regression model with log link, using 
treatment, number of relapses in the previous year before study enrollment, baseline EDSS, 
and baseline number of Gd-enhancing T1 lesions and country (or region) as covariates. In the 
analysis, the response variable is the number of confirmed relapses for each patient. The 
patient’s time in the study (natural log of time in years) is used as an offset variable to obtain 
the ARR, adjusted for the varying lengths of patient’s time in the study (time in years). Study 
centers will be pooled to country or region (based on geographical proximity and/or known or 
expected regional differences in medical care) in order to minimize the impact of 
low-enrolling centers/countries on the analysis (such as nonconvergence of the analysis 
model). Details of pooling will be provided in the statistical analysis plan before database lock. 
The SAS procedure GENMOD (or other software with similar functionality) will be used to 
conduct the analysis.
The treatment effect of each dose of fingolimod versus glatiramer acetate will be presented as 
an ARR ratio with corresponding 95% confidence intervals and p values. The relative 
reduction in ARR will be presented as “percentage change,” calculated as (
/
FTY
GA




-1). 
Multiplicity adjustment for statistical hypothesis testing
The primary hypotheses tests will be tested using a hierarchical step-down procedure to 
control the experiment-wise error rate.
This study is designed to compare each of 2 doses of fingolimod to glatiramer acetate based 
on ARR. There are 2 hypotheses being tested (H01, H02). 
Because it is highly likely that the approved dose of fingolimod (0.5 mg) is more efficacious 
than the lower dose (0.25 mg), the approved dose of fingolimod is initially tested against 
glatiramer acetate at a 2-sided significance level of 0.05. Only if this initial test H01 is 
rejected will H02, the low dose of fingolimod, be tested against glatiramer acetate also at a 
2-sided significance level of 0.05. 
Different scenarios of the anticipated treatment effect between fingolimod 0.5mg or 0.25mg 
versus glatiramer acetate have been evaluated based on the available data on fingolimod and 
the cumulative literature on glatiramer acetate. A 30% treatment benefit of fingolimod 0.5mg 
over glatiramer acetate could be anticipated on the basis of double-blind, 24-months, 
placebo-controlled studies of glatiramer acetate (Johnson et al, 2001) and fingolimod 
[Study CFTY720D2301] alone. However, more recent studies on glatiramer acetate, in a less 
active population, in a total of over 3000 patients, suggest that the efficacy of glatiramer 
acetate on ARR and other endpoints is similar to that of IFN beta-1a SC (REGARDS) or IFN 
beta-1b SC (BEYOND). The observed relapse rates on glatiramer acetate were 0.29 in 
REGARDS and 0.34 in BEYOND, compared to 0.3 (INF beta-1a SC) and 0.33 (INF beta-1b 
SC), respectively. In Study FTY720D2302, a double-blind 1-year study, fingolimod 0.5 mg 
was directly compared to IFN beta-1a IM. The ARR (0.21) in patients treated with fingolimod 
0.5 mg was reduced by 52% compared to the ARR (0.43) in patients treated with INF beta-1a 
IM. Overall, the reduction in ARR in patients treated with fingolimod 0.5 mg compared to 
those treated with glatiramer acetate can be expected in the range of 30% to 50%. For the 
 


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purpose of this study, a 35% lower ARR in patients treated with fingolimod 0.5 mg 
(ARR=0.195) compared to those treated with glatiramer acetate (ARR=0.30) is assumed. 
Fingolimod 0.25 mg has never been tested in a clinical trial. Based on PK/PD modeling a 14% 
higher ARR in patients on fingolimod 0.25 mg compared to those on fingolimod 0.5 mg is 
anticipated. However, the uncertainty of this estimate is substantial. A 95% confidence 
interval from the PK/PD model for the ARR in patients on fingolimod 0.25 mg ranges from 
ARR=0.183 to ARR=0.303. For the purpose of this study, an ARR of 0.225 is assumed in 
patients treated with fingolimod 0.25 mg, which corresponds to an increase in ARR of 
approximately 15% compared to fingolimod 0.5 mg and a relative treatment effect of 25% 
compared to glatiramer acetate.
9.4.3
Handling of missing values, censoring, and discontinuations
All patients in the FAS will be included in the primary analysis, i.e., the number of confirmed 
relapses observed up to the end of patient’s participation in the study. Patients who 
discontinue from study treatment will remain in the study and follow the assessment schedule. 
Relapses will be counted regardless of whether a patient is on or off study drug. Therefore, it 
is expected that all randomized patients can contribute to the primary analysis. The primary 
analysis model adjusts for missing information (early study discontinuations) under some 
statistical assumptions (noninformative dropouts and constant ARR). 
Additionally the following supportive analyses will be conducted:
The primary analysis will be repeated using the per-protocol set to provide an analysis of on-
treatment data from patients who have no major protocol violations. Relapses that occurred 
after permanent discontinuation of study drug will be excluded and log (time on study drug in 
years) rather than log (time on study in years) will be used as the offset variable in the 
negative binomial model with log link.
To assess the impact of missing data on the primary analysis, a sensitivity analysis will be 
performed on ARRs in the full-analysis set using a nonparametric method with imputations. 
The ARRs will be analyzed by means of a rank analysis of covariance (ANCOVA) with 
treatment, and number of relapses in the previous year before study enrollment, baseline 
EDSS, and baseline number of Gd-enhancing T1 lesions as covariates (Stokes 2000). An 
adjustment for country or region can be considered prior to database lock and will be defined 
in the analysis plan. A month-by-month imputation scheme will be used whereby missing data 
in any given month of the study will be imputed with the overall mean number of relapses 
(calculated from all patients across all treatment groups) in the corresponding month. 
A supplementary analysis using the same negative binomial model as in the primary analysis 
to be performed on all relapses (i.e., confirmed and unconfirmed relapses) in the full-analysis 
set will be performed. Additional analyses to further assess the robustness of the results 
maybe prespecified in the statistical analysis plan.
 


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9.5
Analysis of secondary variables
9.5.1
Efficacy variables
All efficacy analyses of secondary variables specified in this section will be conducted on the 
full-analysis set unless otherwise specified.
Magnetic resonance imaging (MRI)
The analyses on MRI parameters will be performed on the full analysis set in the subset of 
patients who have MRI scans done during the study.
The MRI efficacy variables are listed as following: 

Percent change in brain volume from baseline at Month 12 or end of study

Number of new and newly enlarging T2 lesions (compared with baseline MRI scan) at 
Month 12 or at end of study

Proportion of patients free of new/newly enlarging T2 lesions compared to baseline at 
Month 12 or end of study 

Change (and % change) from Baseline in total volume of T2 lesions at Month 12 or end of 
study

Number of new T1 hypointense (acute or chronic) lesions compared to baseline, at 
Month 12 or end of study 

Change and % change from baseline in total volume of T1 hypointense lesions (acute or 
chronic) at Month 12 or end of study

Number of Gd-enhancing T1 lesions at Month 12 or end of study

Total volume of Gd-enhancing T1 lesions at Month 12 or end of study
The number of new or newly enlarging T2 lesions at Month 12 or end of study and number of 
Gd-enhancing T1 lesions at Month 12 or the end of study will be analyzed using a negative 
binomial regression model with log link, using treatment, age, baseline T2 lesion number, 
baseline number of Gd-enhancing T1 lesions, and the number of relapses experienced in the 
previous year before study enrollment as covariates. An adjustment for country or region can 
be considered prior to database lock and will be defined in the analysis plan. For the analysis 
of T2 lesions, an offset variable will be used in the negative binomial analysis to adjust for the 
time in years (since start of study drug).
The proportion type variables will be analyzed using a logistic regression model with 
treatment, age, corresponding baseline value, baseline number of Gd-enhancing T1 lesions, 
and the number of relapses experienced in the previous year before study enrollment as 
covariates. An adjustment for country or region can be considered prior to database lock and 
will be defined in the analysis plan.
The continuous variables (change, percent change, and total volume) will be analyzed using a 
rank ANCOVA model adjusted for treatment, age, corresponding baseline value, and the 
number of relapses experienced in the previous year before study enrollment as covariates. An 
adjustment for country or region can be considered prior to database lock and will be defined 
in the analysis plan. A parametric analysis, especially for the change in brain volume, may be 
specified in the statistical analysis plan prior to database lock. 
 


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Relapses 
All relapse-related analyses use confirmed relapses only, unless otherwise specified. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.5.2
Safety variables
All safety analyses will be conducted on the safety set.
Safety assessments will include: AEs, infections, bradycardia events, laboratory test results, 
vital sign measurements, dermatological examinations, PFTs, ophthalmic examinations, ECG 
data, and C-SSRS.
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having any AE by primary system organ class and preferred term. 
Infections will be considered AEs and summarized with the AEs. Severe AEs, SAEs, 
drug-related AEs, and the AEs leading to premature discontinuation of study drug will be 
presented in a similar format as AEs. Infections will also be summarized separately. Notable 
events will include death, nonfatal SAEs (including infections), and AEs (including 
infections) leading to study drug discontinuation. The frequencies and percentages of patients 
will be tabulated by treatment group.
Laboratory data will be summarized by presenting summary statistics of raw data and change 
from baseline values, by presenting shift tables using clinically notable ranges (Baseline to 
most extreme post-baseline value), and by flagging notable values in data listings. For liver 
function tests, the frequencies and percentages of patients with elevations of 1, 2, 3, 5, and 10 
times the upper limit of normal will be summarized by visit and treatment group.
Estimated creatinine clearance will be summarized by presenting summary statistics by visit 
and treatment group. Change from baseline analyses will be presented by visit and treatment 
group.
Vital sign data will be summarized by presenting summary statistics for change from baseline 
values (both for the period 6 hours after the first dose and for further assessments by visit and 
by end of treatment). The incidence rates of notable vital sign abnormalities will be 
summarized. Further, the frequency distribution for pulse by visit and the frequency 
distribution for percent decline in pulse during first 6 hours will be presented.
Body weight and temperature data will be summarized by presenting summary statistics for 
change from baseline values by visit and at end of treatment. The incidence rates of notable 
weight and temperature abnormalities will be summarized.
Dermatological examination tables and patient listing will be summarized by visit and 
treatment group.
Pulmonary function test data will consist of the following parameters: FEV1, FVC, FEV1/FVC, 
and DLCO. Summary tables and listings will be produced for both absolute values and 
percentage of predicted value when applicable. The data will be summarized by presenting 
 


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summary statistics of change from baseline. A FEV1, FVC, FEV1/FVC, DLCO measurement 
below 80% of predicted will be considered to be abnormal.
The ophthalmic data will be summarized using distribution tables, summary statistics, and 
change from baseline by visit and treatment group. The patient listing will also be provided. 
The incidence (number and percentage) of macular edema in patients with and without 
diabetes will be reported by treatment group. Further analyses can be specified depending on 
the number of patients with diabetes in the trial.
The ECG intervals will be summarized by presenting summary statistics for change from 
baseline values by visit. The (uncorrected) QT interval will be corrected according to the 
Fridericia’s formula. The maximum increase in corrected QT interval from baseline will be 
summarized and the frequencies of patients who fulfill the abnormality criteria based on the 
corrected QT interval will be calculated.
Frequency distribution of treatment-emergent suicidal ideation and behaviors from C-SSRS 
will be summarized. 
Follow-up visit data will be summarized to assess patient’s safety after discontinuation of the 
study drug. 
9.5.3
Resource utilization
Not applicable.
9.5.4
Health related quality of life
Analysis of Treatment Satisfaction Questionnaire for Medication (TSQM v1.4)
The primary analysis for the TSQM will be between group change in Global Satisfaction from 
baseline to Month 12. Analyses of the Effectiveness, Side Effects, and Convenience domains 
will also be conducted. 
For the TSQM, responses to items are summed and transformed so that higher scores indicate 
greater satisfaction. Specifically, TSQM scale scores are computed by adding the items 
loading on each domain. The lowest possible score is subtracted from the composite score and 
divided by the greatest possible score range. This provides a transformed score between 0 and 
1 that is then multiplied by 100. If more than one item is missing from a subscale of the 
TSQM for a particular patient, this subscale should be considered invalid for that respondent.
 


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9.6
Sample size calculation
The study will randomize a total of 1960 patients, and is planned to provide approximately 
90% power for the comparison of fingolimod 0.5 mg to glatiramer acetate at a 2-sided
significance level of 0.05.
The sample size calculation is based on simulations from a negative binomial distribution
with a constant dispersion parameter k. 
The power of the study was evaluated under various ARR assumptions and various dropout 
patterns based on the cumulative literature on glatiramer acetate and the Novartis data on 
fingolimod. The basis of the assumptions for this study and their level of uncertainty are 
presented in Section 9.4.2 under the sub-header “Multiplicity adjustment for statistical 
hypothesis testing”. The anticipated overdispersion parameter (k=0.2231) was observed in the 
Month-12 analysis of Study CFTY720D2301. The anticipated ARR for patients treated with 
0.5 mg fingolimod is µFTY 0.5 mg=0.195, the ARR for those treated with glatiramer acetate is 
µglatiramer acetate=0.30. Therefore, the estimated ARR reduction for fingolimod 0.5 mg versus 
glatiramer acetate is 35%. 
The total sample size of 1960 randomized is predetermined but the exact sample size of each 
arm will depend on when the randomization ratio switch occurs. For example, if the 
randomization ratio is switched when a total of 800 patients have been randomized from an 
original ratio of 1:1:1 for fingolimod 0.25 mg, fingolimod 0.5 mg, or glatiramer acetate, 
respectively to a ratio of 5:3:2, then 847 patients will be randomized to fingolimod 0.25 mg, 
615 patients to fingolimod 0.5 mg and 498 patients glatiramer acetate, which will provide 
 


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more than 90% power to demonstrate superiority of fingolimod 0.5 mg dose versus glatiramer 
acetate in terms of ARR at a 2-sided significance level of 0.05 assuming a 15% drop-out rate. 
The calculations take into account that patients who discontinue prematurely from the study 
can participate with partial data to the primary endpoint.
Fingolimod 0.25 mg has never been studied in a clinical trial in MS. Based on PK/PD 
modeling results, it is anticipated that the ARR in patients treated with fingolimod 0.25mg is 
approximately 15% higher than in those treated with fingolimod 0.5mg. However, the 
uncertainty of this estimate is high; the 95% confidence interval of the estimated ARR in 
fingolimod 0.25 mg group ranges from 0.18 to 0.30. It is therefore anticipated that fingolimod 
0.25mg is less efficacious than fingolimod 0.5mg, but more efficacious than glatiramer 
acetate. In line with the PK/PD modeling the anticipated ARR in patients treated with 
fingolimod 0.25 mg is µFTY 0.25 mg =0.225, which corresponds to a reduction in ARR of 25% in 
patients treated with fingolimod 0.25 mg compared to those treated with glatiramer acetate. 
Following the multiplicity adjustment procedure in Section 9.4.2, the power to detect a 25% 
reduction in ARR for patients treated with fingolimod 0.25 mg compared with patients treated 
with glatiramer acetate is approximately 68% at a 2-sided significance level of 0.05, if the 
primary objective for the fingolimod 0.5-mg dose can be rejected first. If fingolimod 0.25 mg 
is similarly efficacious as fingolimod 0.5 mg (i.e., ARR reduction versus glatiramer acetate is 
35% rather than 25%), the power to detect this treatment effect at a 2-sided significance level 
of 0.05 is approximately 88%. If fingolimod 0.25 mg is similarly efficacious as glatiramer 
acetate (i.e., estimated ARR in the fingolimod 0.25-mg group is at the high end of range 
proposed by the PK/PD model), there will be no significant difference at a 2-sided 
significance level of 0.05.
The statistical software R (Version 2.13.1, open source) and the R library packages “MASS” 
and “PSCL” were used for sample size calculations and power analysis.
9.7
Power for the key secondary hypotheses
Not applicable.
9.9
Interim analysis
Not applicable. No interim analysis is planned for this study.
 


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10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized tripartite guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his or her understanding. If the patient is capable of 
doing so, he or she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e., all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient’s 
source documents. 
 will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH Good Clinical Practice 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 
 before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the 
 monitor after IRB/IEC approval.
10.3
Responsibilities of the investigator and IRB/IEC
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted IRB/IEC before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC must be given to 
Novartis/
 before study initiation. Before study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis/
 monitors, auditors, Novartis/
 
Clinical Quality Assurance representatives, designated agents of Novartis/
 IRBs/IECs, 
and regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Novartis 
 immediately that this 
request has been made.
10.4
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
 


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11
Protocol adherence
Investigators agree that they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation as no authorized deviations are permitted. If 
the investigator feels that a protocol deviation would improve the conduct of the study, this 
must be considered a protocol amendment. Unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC, it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the clinical study report.
11.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for patient safety may be implemented before IRB/IEC 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis should be notified of this action and the IRB/IEC of the study site should be 
informed within 10 working days.
12
References (Available Upon Request)
Atkinson MJ, Sinha A, Hass SL, et al. (2004) Validation of a general measure of treatment 
satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), using a 
national panel study of chronic disease. Health Qual Life Outcomes; 2:12.
Bar-Or A, Fawaz L, Fan B, et al. (2010) Abnormal B-cell cytokine responses a trigger of 
T-cell-mediated disease in MS? Ann Neurol 67(4):452-61.
Bornstein MB, Miller A, Slagle S, et al. (1987) A Pilot Trial of Cop 1 in Exacerbating-
Remitting Multiple Sclerosis N Engl J Med Aug 13;317(7):408-14.
Cadavid D, Wolansky LJ, Skurnick J, et al. (2009) Efficacy of treatment of MS with 
IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study , Neurology., 
72(23):1976-1983.
Cohen JA, Barkhof F, Comi G, et al. (2010) Oral fingolimod or intramuscular interferon for 
relapsing multiple sclerosis; N. Engl. J. Med. 362(5), 402-15. Fingolimod Phase III trial.
Darlington PJ, Touil T, Doucet J-S, et al. (2013) Diminished Th17 (not Th1) responses 
underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation. 
Ann Neurol 73(3):341-354.
 
Johnson KP, Brooks BR, Cohen JA, et al.; The copolymer 1 MS study Group. (2001)
Copolymer-1 reduces relapse rate and improves disability in relapsing remitting multiple 
 


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sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. 1995.
Neurology: 57 (12 Suppl 5):S16-24.
Kappos L, Radue EW, O'Connor P, et al. (2010) A placebo-controlled trial of oral fingolimod 
in relapsing multiple sclerosis. N. Engl. J. Med. 362(5), 387–401. Fingolimod Phase III trial.
Kebir H, Kreymborg K, Ifergan I, et al. (2007) Human Th17 lymphocytes promote 
blood-brain barrier disruption and central nervous system inflammation Nature Medicine
13(10) 1173-5.
Keegan BM, Noseworthy JH. (2002) Multiple sclerosis. Annu Rev Med.;53:285-302.
Keene CD, Sonnen JA, Swanson PD, et al. (2007) Neural transplantation in Huntington 
disease: long-term grafts in two patients. Neurology 68(24):2093–8.
MacIntyre N, Crapo RO, Viegi G, et al. (2005). Standardisation of the single-breath 
determination of carbon monoxide uptake in the lung. Eur Respir J 26(4):720-35.
McDonald WI, Compston A, Edan G, et al. (2001) Recommended diagnostic criteria for 
multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple 
sclerosis. Ann Neurol 50(1):121-7.
Mehling M, Lindberg R, Raulf F, et al. (2010) Th17 central memory T cells are reduced by 
FTY720 in patients with multiple sclerosis Neurology 75(5): 403-10.
Mikol DD, Barkhof F, Chang P, et al.; REGARD study group. (2008) Comparison of 
subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple 
sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a 
multicentre, randomised, parallel, open-label trial. Lancet Neurol 7(10), 903-14.
Miller MR, Crapo R, Hankinson J, et al. (2005a) General considerations for lung function 
testing. Eur Respir J 26(1):153-61.
Miller MR, Hankinson J, Brusasco V, et al. (2005b) Standardisation of spirometry. Eur Respir 
J 26(2):319-38.
O'Connor P, Filippi M, Arnason B, et al. (2009) 250 microg or 500 microg interferon beta-1b 
versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, 
randomised, multicentre study; Lancet Neurol Oct:8(10):889-97.
Panitch H, Goodin DS, Francis G, et al.; EVIDENCE Study Group; Evidence of Interferon 
Dose-response: European North American Compartative Efficacy; University of British 
Columbia MS/MRI Research Group. (2002) Randomized, comparative study of interferon 
beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology 59(10):1496-506.
Polman CH, Reingold SC, Edan G, et al. (2005) Diagnostic criteria for multiple sclerosis: 
2005 revisions to the ‘‘McDonald Criteria.’’ Ann Neurol 58(6):840–6.
Polman CH, Reingold SC, Banwell B, et al. (2011) Diagnostic criteria for multiple sclerosis: 
2010 revisions to the McDonald criteria. Ann Neurol 69(2):292-302.
Stokes ME, Davis CS, Koch GG. (2000) Categorical data analysis using the SAS system. SAS 
Institute, Inc., Cary, N.C.
 
 
 


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Tzartos JS, Friese MA, Craner MJ, et al. (2008) Interleukin-17 production in central nervous 
system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. 
Am J Pathol 172(1):146-155.
 


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13
Appendices
Appendix 1: Clinically notable laboratory values and vital signs
Only selected lab parameters identified as notable which have been shown to be sensitive to 
fingolimod exposure are included.
CRITERIA FOR NOTABLE LABORATORY ABNORMALITIES
Notable Values
Laboratory Variable
Standard Units
SI Units
LIVER FUNCTION AND RELATED VARIABLES
SGOT (AST)
>82 U/L
>82 U/L
SGPT (ALT)
>90 U/L
>90 U/L
Total bilirubin
2.0 mg/dL
34.2 mol/L
Alkaline phosphatase
>280 U/L
>280 U/L
RENAL FUNCTION / METABOLIC AND ELECTROLYTE VARIABLES
Glucose `
200 mg/dL
11.11 mmol/L
Creatinine
2.0 mg/dL
176 umol/L
Amylase
300 U/L
300 U/L
Cholesterol
240 mg/dL
6.21 mmol/L
Triglycerides
≥300 mg/dL
≥3.39 mmol/L
Blood urea nitrogen (BUN)
≤2 mg/dL
≥30 mg/dL
≤0.7 mmol/L
≥10.7 mmol/L
Sodium
<125 mEq/L
>154 mEq/L
<125 mmol/L
>154 mmol/L
Chloride
≤85 mEq/L
≥119mEq/L
≤85 mmol/L
≥119 mmol/L
Potassium
≤3.0 mEq/L
≥6.0 mEq/L
≤3.0 mmol/L
≥6.0 mmol/L
Magnesium
≤1.0 mg/dL 
≥3.0 mg/dL
≤0.40 mmol/L
≥1.23 mmol/L
Calcium
≤7.5 mg/dL
≥11.6 mg/dL
≤1.87 mmol/L
≥2.89 mmol/L
Phosphate
≤2.0 mg/dL
≥5.3 mg/dL
≤0.65 mmol/L
≥1.71 mmol/L
 


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


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Appendix 2:  2010 Revisions to the McDonald diagnosis criteria for MS
Guidelines from International Panel on the diagnosis of MS
(McDonald et al, 2001; Polman et al, 2005; Polman et al, 2011)
Clinical Presentation
Additional Data Needed for MS Diagnosis
2 or more attacksa; objective
clinical evidence of 2 or more
lesions or objective clinical
evidence of 1 lesion with
reasonable historical evidence
of a prior attackb
Nonec
Two or more attacksa; objective clinical 
evidence of 1 lesion
Dissemination in space, demonstrated by: 
≥1 T2 lesion in at least two out of four MS-
typical regions of the CNS (periventricular, 
juxtacortical, infratentorial, or spinal cord)d
OR
Await a further clinical attacka implicating a 
different CNS site
One attacka; objective clinical evidence of 2 or
more lesions
Dissemination in time, demonstrated by:
Simultaneous 
presence 
of 
asymptomatic 
gadolinium-enhancing 
and 
non-enhancing 
lesions at any time.
OR
A new T2 and/or gadolinium-enhancing 
lesion(s) on follow-up MRI, irrespective of its 
timing with reference to a baseline scan.
OR
Await a further clinical attacka
 


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One attacka; objective clinical evidence of 1 
lesion (clinically isolated syndrome)
Dissemination 
in 
space 
and 
time, 
demonstrated by:
For DIS
≥1 T2 lesion in at least two out of four MS-
typical regions of the CNS periventricular, 
juxtacortical, infratentorial, or spinal cord)d
OR
Await a second clinical attacka implicating a 
different CNS site
AND
For DIT
Simultaneous 
presence 
of 
asymptomatic 
gadolinium-enhancing 
and 
non-enhancing 
lesions at any time.
OR
A new T2 and/or gadolinium-enhancing 
lesion(s) on follow-up MRI, irrespective of its 
timing with reference to a baseline scan.
OR
Await a second clinical attacka
If the Criteria are fulfilled the diagnosis is MS.
a.An attack (relapse; exacerbation) is defined this as patient-reported or objectively observed events typical of an acute 
inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours, in the absence of fever 
or infection. It should be documented by contemporaneous neurological examination, but some historical events with 
symptoms and evolution characteristic for MS, but for which no objective neurological findings are documented, can provide 
reasonable evidence of a prior demyelinating event. Reports of paroxysmal symptoms (historical or current) should, however, 
consist of multiple episodes occurring over not less than 24 hours. Before a definite diagnosis of MS can be made, at least 
one attack must be corroborated by findings on neurological examination, visual evoked potential (VEP) response in patients 
reporting prior visual disturbance, or MRI consistent with demyelination in the area of the CNS implicated in the historical 
report of neurological symptoms.
bClinical diagnosis based on objective clinical findings for two attacks is most secure. Reasonable historical evidence for one 
past attack, in the absence of documented objective neurological findings, can include historical events with symptoms and 
evolution characteristics for a prior inflammatory demyelinating event; at least one attack, however, must be supported by 
objective findings.
cNo additional tests are required. However, it is desirable that any diagnosis of MS be made with access to imaging based on 
these Criteria. If imaging or other tests (for instance, CSF) are undertaken and are NEGATIVE, extreme caution needs to be 
taken before making a diagnosis of MS and alternative diagnoses must be considered. There must be no better explanation for 
the clinical presentation and objective evidence must be present to support a diagnosis of MS.
dGadolinium-enhancing lesions are not required; symptomatic lesions are excluded from consideration in subjects with 
brainstem or spinal cord syndromes.
 


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Appendix 3:  Guidance on safety monitoring
Patients whose blood pressure reading is ≥140 (systolic) and/or ≥90 mm Hg (diastolic) should 
have their blood pressure retested after 15 minutes of rest. If the blood pressure is still 
elevated, they should be followed up in one month by an unscheduled visit if the scheduled 
visit is not due. Should systolic BP ≥140 and/or diastolic BP ≥90 mm Hg values be confirmed 
at the second visit, the patient should be referred to his primary care physician, an 
independent internist or to the specialty hypertension clinic for evaluation, diagnosis and 
treatment of hypertension.
Patients with BP values of >160/100 mm Hg (confirmed by repeat testing) at any visit during 
the study should be immediately referred as above for evaluation, diagnosis and treatment of 
hypertension. 
Newly diagnosed hypertension as well as an aggravation of a preexisting condition must be 
reported as an AE and appropriate antihypertensive medication/dosage adjustment must be 
considered by the investigator.
Guidance on monitoring of patients with elevated liver function tests
In case of detection of elevated ALT/AST values >2 and <5 times the ULN range, additional 
blood chemistry panel including ALT, AST, AP, GGT, total and conjugated bilirubin, 
albumin may be performed at the investigator’s discretion.
If ALT/AST values reach 5 times the ULN, confirmed upon repeat testing within two weeks 
of the initial result or sooner at the discretion of the investigator, the study drug must be 
permanently discontinued. Patients who develop symptoms suggestive of hepatic dysfunction 
such as unexplained vomiting or jaundice, should have liver enzymes checked and fingolimod 
should be discontinued if significant liver injury is confirmed. 
In case of isolated elevation of bilirubin over 2.0 mg/dl (34.2 umol/L) unless in context of 
Gilbert’s syndrome, confirmed upon repeat testing within two weeks of the initial result, the 
investigator must discontinue the study drug. Additional evaluations may be performed at the 
discretion of the investigator.
For any unscheduled laboratory assessments performed locally, an identical sample should 
also be sent to the central laboratory for analysis and capture in the central database. 
An interruption or discontinuation of the study drug should be clearly documented and 
reflected on Dosage Administration Record CRF. AE/SAEs need to be filed as appropriate.
Guidance on monitoring of patients with notable lymphopenia
Fingolimod results in sequestration of a proportion of the circulating lymphocytes in lymph 
nodes with resultant reduction in circulating lymphocyte counts. Average circulating 
lymphocytes counts are expected to be around 0.5 -0.6 x109 /L or 500- 600 cells/mm3. Please 
see Investigator Brochure for more details. As such, the absolute total WBC, neutrophil and 
lymphocyte counts will be measured at each visit by the central laboratory, but will be 
reported blinded for subjects randomized to fingolimod. Lymphocyte counts below 0.2x109/L 
in patients randomized to fingolimod treatment are reported unblinded and require repeat 
 


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testing within 2 weeks. If the repeat test confirms lymphocyte counts below 0.2x109/L, the 
investigator should perform at least monthly retests. Results will only be reported blinded 
again once they reach 0.6x109/L.
If the repeat test confirms the lymphocyte count is below 0.2x109/L or 200 cells/mm3 and 
there are no signs or symptoms of infection, the patient can continue on study medication at 
the discretion of the investigator with regular monitoring for signs of infections. 
If the patient presents with signs of infection and the lymphocyte count is below 0.2x109/L, 
the study drug must be temporarily interrupted, and the investigator should consider treatment 
with a specific therapy on the basis of the clinical diagnosis in consultation with an infectious 
disease specialist. Reinitiation of the study drug can only be considered once the lymphocyte 
count reaches 600 cells/mm3 as confirmed by the central laboratory and after discussion with 
the Medical Monitor.
If the patient is randomized to the glatiramer acetate treatment group and presents with 
significant lymphopenia (<50% baseline) confirmed on repeat test by central laboratory 
within two weeks, study drug must be interrupted and further diagnostic work-up needs to be 
initiated. The investigator should only consider re-initiation of the glatiramer acetate after a 
thorough diagnostic workup has been performed, diagnosis/cause for the lymphopenia has 
been established, treatment has been initiated as adequate, and only after discussion with 
Medical Monitor and if the patient shows no signs or symptoms of infection or malignancy.
Guidance on monitoring of patients with symptoms of neurological 
deterioration, inconsistent with MS course
Should a patient develop any manifestations that, in opinion of the investigator, are atypical
for multiple sclerosis including unexpected neurological or psychiatric symptom/signs (e.g. 
rapid cognitive decline, behavioral changes, cortical visual disturbances or any other 
neurological cortical symptoms/sign), or any symptom/sign suggestive of an increase of 
intracranial pressure or accelerated neurological deterioration, the investigator should 
schedule a complete physical and neurological examination and an MRI as soon as possible 
and before beginning any steroid treatment. Conventional MRI as defined in the protocol as 
well as Fluid-attenuated Inversion Recovery (FLAIR) and Diffusion-weighted imaging (DWI) 
sequences are recommended for differential diagnosis of Posterior reversible encephalopathy 
syndrome. The MRI must be evaluated by the local neuroradiologist. The investigator will 
contact the Medical Advisor at Novartis to discuss findings and diagnostic possibilities as 
soon as possible. AE/SAEs need to be filed as appropriate.
In case of new findings in the MRI images in comparison with the previous available MRI 
which are not compatible with MS lesions, the study drug will be discontinued and other 
diagnostic evaluations need to be performed at the discretion of the investigator. In case of 
presence of new hyperintense T2-weighted lesions in the MRI which may be infectious in 
origin it is recommended to collect a cerebrospinal fluid sample if indicated. Analysis of the 
CSF sample including cellular, biochemical and, microbiological analysis (e.g. herpes virus, 
JC virus), to confirm/exclude an infection (e.g. PML) should be performed. In the event of 
suspected CNS infection, a CSF aliquot should be sent to a central laboratory (designated by 
the sponsor) for confirmatory testing.
 


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Only when the differential diagnosis evaluations have excluded other possible diagnosis than 
MS and after discussion with the Medical Advisor at Novartis, the study drug may be 
restarted.
Guidance on monitoring of patients with infections
All infections that develop during the study will be reported as AEs. Investigators are 
requested to specifically ask about infections at each visit. Treatment and additional 
evaluations will be performed at discretion of the investigator. 
The investigator should be vigilant for risk of infections including opportunistic infections due 
to bacterial infections (e.g., atypical mycobacteria), viral infections (e.g., HSV, VZV, JCV), 
or fungal infections (e.g., cryptococcus agents) and should remind the patient of the risk of 
infections and to instruct them to promptly report any symptoms of infections to the 
investigator. The patients must also be reminded to always carry their Patient Information 
Card (with site contact information and which identifies them as participants in a clinical 
study with an agent with potential immunosuppressive effects) and to show this to any local 
healthcare provider they may consult and ask that the investigator be contacted. 
When evaluating a patient with a suspected infection, the most sensitive tests available should 
be used (i.e. that directly detect the pathogen, as with PCR). 
The investigator should consider early treatment with specific therapy on the basis of clinical 
diagnosis or suspicion thereof (e.g., antiviral treatment for herpes simplex or VZV; treatment 
for cryptococcus) in consultation with infectious disease experts, as appropriate. Investigators 
should be aware that in the post-marketing setting with fingolimod, isolated cases of 
cryptococcal meningitis have been reported. Patients reporting symptoms and signs (such as, 
but not limited to, headache accompanied with stiff neck, sensitivity to light, fever, confusion, 
tiredness, body aches, chills, vomiting, and/or nausea) consistent with meningitis should 
undergo prompt diagnostic evaluation. If (cryptococcal) meningitis is diagnosed, appropriate
antibiotic treatment should be initiated as soon as possible. The investigator should inform the 
Novartis medical expert and the CRO’s medical expert of any such cases.
Suspension of treatment with fingolimod should be considered if a patient develops a serious 
infection, and consideration of benefit-risk should be undertaken prior to re-initiation of 
therapy.
Investigators should consider the added immunosuppressive effects of corticosteroid therapy 
for treatment of MS attack/relapse and increase vigilance regarding infections during such 
therapy and in the weeks following administration.
Patients should be evaluated for evidence of immunity to VZV based on any of the following:

Laboratory evidence of immunity or laboratory confirmation of disease

Diagnosis or verification of a history of VZV or herpes zoster by a health care 
provider
To verify a history of VZV, health care providers should inquire about:
 


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
An epidemiologic link to another typical VZV case or to a laboratory confirmed case, 
or

Evidence of laboratory confirmation, if testing was performed at the time of acute 
disease
The VZV vaccination of antibody-negative patients should be considered prior to 
commencing treatment with fingolimod, following which initiation of study drug should be 
postponed for at least 1 month to allow full effect of vaccination to occur. 
Serology testing for antibody status of HSV-1 and HSV-2 and rubeola (measles) is performed 
at screening to profile infection risk in study patients. The investigator should inform the 
patients of their immune status based on these serology results and of the potential risks of 
primary infections or viral reactivation while taking fingolimod.
A positive IgG antibody test result does not indicate active infection per se, but only evidence 
of exposure to viral antigens via past infection or vaccination. These patients may however, be 
at risk for viral reactivation, which may manifest as:  

VZV virus IgG positive: Shingles

HSV-1 IgG positive: Cold sores

HSV-2 IgG positive: Herpes genitalis
The investigator should instruct the patient to be alert to and report any symptoms or signs 
suggestive of cold sores, genital ulcers or shingles, so that appropriate anti-viral treatment can 
be initiated in consultation with a local infectious disease expert (if needed). 
A negative IgG antibody test result for HSV-1, HSV-2, and rubeola places patients at risk for 
more severe and atypical manifestations of primary infection in the event they are exposed to 
these viruses while they are immunosuppressed (taking study drug and/or corticosteroids).  
Patients who are negative for HSV-1 IgG, HSV-2 IgG and rubeola antibodies should be 
instructed to promptly report any exposure to these viruses i.e. to a person with cold sores, 
herpes genitalis, respectively. In case of exposure, early treatment with appropriate antiviral 
drugs should be considered in consultation with a local infectious diseases expert.
It is also important to ask the patient receiving fingolimod to report if they are exposed to 
anyone who has recently received a live or live attenuated vaccine and manifested a skin rash 
after the vaccination so that it can be decided, in consultation with an infectious disease expert, 
if antiviral therapy is warranted. 
It should be noted that live or live attenuated vaccines are prohibited while fingolimod 
patients are taking study drug and for 8 weeks after study drug discontinuation.
Guidance on monitoring pulmonary function 
Patients reporting any respiratory symptoms such as dyspnea, shortness of breath, chest 
tightness, wheezing should be seen at an unscheduled visit for clinical assessment. A full 
pulmonary function test (FEV1, FVC, and DLCOc [i.e., DLCOcorrected]) and a bronchodilator 
reversibility test need to be performed, preferably on the same day. If PFTs demonstrate 
reduction of FEV1 or FVC values to 80% or below of baseline values, initiation of treatment 
with bronchodilators will be considered. 
 


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In case of reduction of FEV1, FVC, and/or DLCOc below 80% of baseline values, the patient’s 
pulmonary status will require a follow-up as soon as possible within no more than 1 month, 
including history of respiratory symptoms (eg, dyspnea, shortness of breath, chest tightness, 
wheezing), physical examination, FEV1, FVC, DLCOc measurement, and a bronchodilator 
reversibility test. 
Should repeat PFT values (FEV1, FVC, and/or DLCOc) remain below 80% of baseline values 
or should a worsening of the previously reported respiratory symptoms be observed, the 
patient will be referred to pneumologist (pulmonologist) for further evaluation, including 
chest HRCT and treatment. A standard referral letter explaining a reason for referral should be 
accompanied by the sponsor’s information letter about the investigational drug (FTY720).
In case of reduction of FEV1, FVC, and/or DLCOc below 60% of baseline value in any visit, 
the study drug should be discontinued and the patient must be immediately referred to 
pneumologist (pulmonologist) for further evaluation, including chest HRCT and treatment. 
In case of persistent reduction of FEV1, FVC, and/or DLCOc below 80% over 3-month period 
despite appropriate treatment, the Primary Treating Physician should consider an interruption 
of the study drug. This decision may be discussed with Medical Monitor.
 


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Appendix 4:  Guidance for ophthalmic monitoring
In MS studies, macular edema was reported in 0.4% of patients receiving fingolimod 0.5 mg, 
and the majority occurred in the first 3-4 months. Some patients presented with blurred vision 
or decreased visual acuity, but others were asymptomatic and diagnosed during routine 
ophthalmological 
examinations. 
Macular 
edema 
generally 
improved 
or 
resolved 
spontaneously after discontinuation; continuation of fingolimod in patients with macular 
edema has not been evaluated. Patients with diabetes mellitus or with uveitis are at increased 
risk of macular edema. Fingolimod has not been studied in multiple sclerosis patients with 
concomitant diabetes mellitus. 
Ophthalmic examinations, including optical coherence tomography (OCT) and fluorescein 
angiography (FA), for assessment of macular edema are scheduled as outlined in Table 6-1.
Similar assessments must be performed as part of an unscheduled ophthalmology visit for any 
patient who presents with new visual symptoms. If patients report visual disturbances at any 
time while on therapy, evaluation of the fundus, including the macula, should be carried out 
by an ophthalmologist.
Guidance on monitoring patients for possible macular edema
If macular edema is suspected during the study, an OCT must be performed as a confirmatory 
test. If macular edema diagnosis is confirmed on OCT, study drug must be permanently 
discontinued.
These patients must be followed-up with monthly ophthalmologic evaluations, including OCT, 
until such time as resolution is confirmed or no further improvement is expected by the 
ophthalmologist (based on a follow-up period of not less than three months). If the patient 
does not show definite signs of improvement on examination by specialist testing (e.g., OCT) 
after 6-8 weeks after discontinuation of study drug, then therapy for macular edema in 
conjunction with an ophthalmologist experienced in the management of this condition should 
be initiated and further managed by the ophthalmologist until either resolution of the macular 
edema or there is absence of any evidence of further improvement.
The discontinuation of the study drug should be clearly documented and reflected on Dosage 
Administration Record CRF. AE/SAEs need to be filed as appropriate. For patients 
discontinuing study drug due to a diagnosis of macular edema, copies of the colored OCT as 
well as source documents of ophthalmic examination should be kept at the site as source 
documents. These documents may need to be submitted for review by an independent panel if 
needed. 
Guidance on monitoring patients with uveitis
Patients with a history of uveitis or findings compatible with active uveitis at screening can 
enter the study given that there is no evidence of macular edema in the screening ophthalmic 
examination.
In order to specifically assess the risk of macular edema in the MS population with co-
existing uveitis, each patient with findings in any ophthalmic examination compatible with 
active uveitis (e.g., significant anterior chamber cell or flare, vitreous cell or flare, pars 
 


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planitis, vasculitis, chorioretinitis) under the discretion of the investigator should undergo 
more frequent ophthalmic examinations. It is the discretion of the investigator to determine 
the frequency of these ophthalmic examinations. Adjustments to the schedule can be made to 
align these evaluations with other planned study visits. 
A suspicion of macular edema will require an OCT to be performed (refer to Guidance for 
monitoring of patients with macular edema above).
 


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SAP_001.pdf: 
Clinical Development 
FTY720D (fingolimod) 
Clinical Trial Protocol CFTY720D2312 / NCT01633112
A 12-month, randomized, rater- and dose-blinded study to 
compare the efficacy and safety of fingolimod 0.25 mg 
and 0.5 mg administered orally once daily with glatiramer 
acetate 20 mg administered subcutaneously once daily in 
patients with relapsing-remitting multiple sclerosis 
RAP Module 3 – Detailed Statistical Methodology 
Author: 
 
 
Document type: 
RAP Documentation 
Document status: 
Final Version 2.6 Addendum 1 
Release date: 
02Nov2018 


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RAP Module 3 
 
Protocol No. CFTY720D2312 
 
Number of pages: 
79 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
 
Document History – Changes compared to previous version of RAP module 3. 
Version 
Date 
Changes 
Final V2.1 
28MAY2014 
Changes to follow updated protocol amendment 1 
Final V2.2  
06APR2015 
Added sensitivity analysis to the primary analysis by excluding one 
misconduct site 
 
26AUG2015 
Updated per protocol final amendment 2 
Final V2.3 
17FEB2017 
Updated the sample size calculation per study early termination 
approved by FDA in December 2016 
 
24MAR2017 
 
Final V2.4 
20OCT2017 
Added two Canada provinces (British Columbia and Manitoba) in 
Section 3.9 (Pooling of centers). 
Updated the sections related to C-SSRS per specific eCRF 
implemented via IVRS for this study. There is no visit information in 
IVRS data, so a visit window is added for C-SSRS.  
 
06DEC2017 
Clarified nominal visits for dermatology and OCT assessment to be 
consistent with the TLF shells.  
 
28DEC2017 
Updates to MRI model specifications to match with the protocol. 
 
10JAN2018 
Vital signs: updated per the study data collection specifics (sitting for 
old CRFs and supine/standing for later CRFs). Data summaries are 
updated to present for each position separately. 
 
10JAN2018 
Bradycardia event from first dose monitoring: Clarified that 
bradycardia events that do not have symptoms are not collected in 
the bradycardia CRFs and will be identified from the Adverse Event 
CRF. 
 
07FEB2018 
Added a sentence to specify MedDRA version.  
 
 
Final sample number is updated to 1064, instead of 1063. 
 
 
Added wording about two discontinuation listings per FDA request. 
 
09FEB2018 
Moved C-SSRS section to Safety Section 8.9. 
 
02MAY2018 
Clarified last dose date definition. 
 
 
Clarified regular ECG summaries at Baseline and Month 12/EOT to 


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Protocol No. CFTY720D2312 
 
Version 
Date 
Changes 
align with RAP M7.1 and study protocol.  
Added the decision about following the old Novartis PD process, 
instead of the new Novartis PD process.  
Removed the figures for individual subjects meeting liver function 
safety criteria and those meeting hematology notable criteria as they 
do not provide any additional information to the existing abnormality 
tables per dry run 1 team decision. 
Removed the section about baseline comparability tests to be 
consistent with the recently completed FTY2201 study and 
considering this is a randomized study. 
 
04MAY2018 
 
 
 
 
 
 
 
 
 
 
.   
 
10MAY2018     Updated Section 6 per 
 comments (NVS). 
 
 
Updated to remove ‘unenhanced’ in the label for T1 lesion to be 
consistent with source data label and also per 
 comment 
(NVS). 
 
14MAY2018 
Updated Section 3.9 Pooling of Centers by added a few more US 
states per the final clinical document.  
Added a complete list of centers with geographic locations and 
region classification in Appendix 1. 
 
Final 2.5 
22Aug2018 
For PFT section, a note is added to clarify how to handle a few 
outliers (unrealistic values) in the final analysis. 
 
28Aug2018 
Section 8.1.2.1 Occurrence of SAEs and NSAEs: Added the entire 
section to add two tables to meet the CTSD requirement. 
Section 8.1.3 Data summaries for AEs: Added two bullets for the two 
new tables described in Section 8.1.2.1.    
 
10Sep2018 
Section 3.6 Study Medication: Added data handling rule for partial 
end date for the last dosing interval.  
Section 3.8.7 Last dose day of randomized study medication: Added 
data handling rule for partial or completely missing last dose date on 
the CMP panel.  
Section 4.1.3 Time in study (years) for aggregate ARR: Updated to 
use the new definition by excluding FU visits and removing the 
truncation at 367 days. 
Section 4.2.1.2 Supportive analysis: Moved the old definition for time 
in study for ARR calculation to this section and kept it as one 


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Protocol No. CFTY720D2312 
 
Version 
Date 
Changes 
supportive analysis. 
Section 4.2.1.2 Supportive analysis: Added additional sensitivity 
analysis by defining confirmed relapse strictly based on EDSS 
scores. 
Section 4.2.2.1 MRI: Added sensitivity analyses to exclude baseline 
assessments > 45 days before randomization and end of treatment 
assessments > 45 days after last dose.  
 
13Sep2018 
Section 8.1 Adverse Events: Added summaries for risk AEs and 
updated wording for occurrence rate of AEs to be consistent with 
study D2311. 
Final 2.6  
02Nov2018 
Section 4.2.2.1: Added new analyses for annualized rate of brain 
atrophy (ARBA) at Month 12/end of treatment. This is to adjust for 
study duration and also other MRI covariates due to some 
differences between treatment groups.  
 
 
 


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Protocol No. CFTY720D2312 
 
Table of contents 
Table of contents ............................................................................................................................. 5 
List of tables ..................................................................................................................................... 8 
1 
Statistical methods planned in the protocol and determination of sample size .......................... 10 
2 
Statistical and analytical plans ....................................................................................................... 10 
3 
Subjects and treatments, general rules and definitions................................................................ 11 
3.1 
Analysis sets ...................................................................................................................... 11 
3.2 
Subject disposition ............................................................................................................ 11 
3.3 
Protocol deviations ........................................................................................................... 12 
3.4 
Background and demographic characteristics.................................................................. 13 
3.5 
MS disease and medical history ....................................................................................... 14 
3.6 
Study medication .............................................................................................................. 15 
3.7 
Concomitant medication/therapy .................................................................................... 16 
3.8 
Visit windows and cutoffs for efficacy and safety analyses.............................................. 18 
3.8.1 
Study Day 1 and other study days .................................................................. 18 
3.8.2 
Screening/Baseline ......................................................................................... 19 
3.8.3 
Nominal visits and visit windows .................................................................... 19 
3.8.3.1 
Nominal visits................................................................................................... 19 
3.8.3.2 
Visits windows ................................................................................................. 20 
3.8.4 
Time points for first dose monitoring ECG and Vital signs ............................. 22 
3.8.5 
Safety data cutoff and visit windows for summaries on follow-up set .......... 22 
3.8.6 
Multiple assessments within visit windows ................................................... 23 
3.8.7 
Last dose day of randomized study medication ............................................. 23 
3.9 
Pooling of centers ............................................................................................................. 24 
4 
Efficacy evaluation ......................................................................................................................... 24 
4.1 
Primary and key secondary efficacy variables .................................................................. 24 
4.1.1 
Primary efficacy variable ................................................................................ 24 
4.1.2 
Key secondary efficacy variable ...................................................................... 25 
4.1.3 
Time in study (years) for aggregate ARR ........................................................ 25 
4.2 
Statistical methodology .................................................................................................... 25 
4.2.1 
Primary analysis .............................................................................................. 25 
4.2.1.1 
Multiplicity adjustment for statistical hypothesis testing ............................... 26 


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4.2.1.2 
Supportive analyses of primary endpoint........................................................ 27 
4.2.1.3 
Handling dropouts in ARR calculations ............................................................ 29 
4.2.1.4 
Missing MS relapse dates ................................................................................ 31 
4.2.2 
Analyses of secondary 
 variables .......................................... 31 
4.2.2.1 
Magnetic resonance imaging (MRI) ................................................................. 32 
4.2.2.2 
Relapses ........................................................................................................... 34 
 
 36 
 
 37 
4.2.2.5 
EDSS Scores ...................................................................................................... 38 
 
 38 
 
 38 
7 
Health-related Quality of Life (QoL) .............................................................................................. 40 
 
 40 
 
 40 
 
 40 
 
 41 
 
 41 
7.3 
TSQM (Version 1.4) ........................................................................................................... 41 
8 
Safety evaluation ........................................................................................................................... 42 
8.1 
Adverse events ................................................................................................................. 43 
8.1.1 
Adverse event date imputation ...................................................................... 43 
8.1.2 
Adverse events ............................................................................................... 44 
8.1.2.1 
Occurrence of SAEs and NSAEs (non-serious AEs) ........................................... 45 
8.1.3 
Data summaries for AEs .................................................................................. 45 
8.2 
Laboratory data ................................................................................................................ 46 
8.2.1 
SI Units ............................................................................................................ 46 
8.2.2 
Clinically notable criteria ................................................................................ 46 
8.2.3 
Data Summaries for lab tests.......................................................................... 50 
8.3 
Vital signs .......................................................................................................................... 51 
8.3.1 
Vital signs measurements ............................................................................... 51 
8.3.2 
Vital signs notable criteria .............................................................................. 51 


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8.3.3 
Data summaries for vital signs ........................................................................ 52 
8.4 
Electrocardiograms (ECG) ................................................................................................. 52 
8.4.1 
Corrected QT interval ..................................................................................... 53 
8.4.2 
Abnormality criteria for corrected QT interval ............................................... 53 
8.4.3 
ECG findings .................................................................................................... 53 
8.4.4 
Data summaries for ECG data ......................................................................... 53 
8.5 
Pulmonary function tests (PFT) ........................................................................................ 54 
8.5.1 
Predicted values and units of PFTs ................................................................. 54 
8.5.2 
Percent predicted PFTs ................................................................................... 54 
8.5.3 
Data summaries for PFTs ................................................................................ 55 
8.6 
Ophthalmic evaluations .................................................................................................... 55 
8.6.1 
Data summaries for ophthalmic evaluations .................................................. 56 
8.7 
Dermatology assessment.................................................................................................. 56 
8.8 
First dose (second dose or restart dose) of fingolimod monitoring ................................. 57 
8.8.1 
Vital signs ........................................................................................................ 57 
8.8.2 
ECG .................................................................................................................. 57 
8.8.3 
Dose monitoring experience .......................................................................... 57 
8.8.4 
Data summaries for first dose monitoring ..................................................... 57 
8.9 
Columbia Suicide Severity Rating Scale (C-SSRS) .............................................................. 58 
9 
Interim analyses............................................................................................................................. 60 
10 Determination of sample size ........................................................................................................ 60 
11 Documentation of changes from the protocol .............................................................................. 61 
12 Clinical Study Report -  Appendix 16.1.9 Documentation of statistical methods ......................... 62 
12.1 
Statistical methods and analysis outputs ......................................................................... 62 
12.1.1 
Statistical methods ......................................................................................... 62 
12.1.1.1 
Negative binomial regression model ............................................................... 62 
12.1.1.2 
Rank Analysis of Covariance (ANCOVA) and Rank Analysis of Variance 
(ANOVA) 
64 
12.1.1.3 
Logistic regression for proportion variables .................................................... 66 
12.1.1.4 
Survival analysis for time to event variables ................................................... 67 
12.1.1.5 
Between-treatment group comparisons for other efficacy variables ............. 70 
12.1.1.6 
Analysis of Covariance (ANCOVA) for quality of life (QoL) variables ............... 71 


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12.1.1.7 
Wilcoxon sign test for quality of life (QoL) variables ....................................... 72 
12.1.2 
Statistical analysis outputs ............................................................................. 73 
13 References ..................................................................................................................................... 73 
14 Appendices .................................................................................................................................... 74 
14.1 
Appendix 1: Geographic location (state/providence and country) of the study 
centers .............................................................................................................................. 74 
 
List of tables 
Document History – Changes compared to previous version of RAP module 3. .................................... 2 
Table 1-1 The analysis sets and severity codes ..................................................................................... 12 
Table 1-1a The derivation formula for creatinine clearance................................................................. 13 
Table 1-2 Display of drug names ........................................................................................................... 15 
Table 1-3 Definitions of time-intervals used to summarize exposure to study medication ................. 16 
Table 1-4 CMD date imputation ............................................................................................................ 17 
Table 2-1 Visit windows for vital signs and laboratory values .............................................................. 20 
Table 2-2 Visit windows for PFTs ........................................................................................................... 21 
Table 2-3 Visit windows for ophthalmologic examination (excluding OCT) ......................................... 21 
Table 2-4 Visit windows for ECG ........................................................................................................... 21 
Table 2-5 Visit windows for C-SSRS ....................................................................................................... 21 
Table 3-1 Primary efficacy endpoint, supportive endpoints & analyses ............................................... 27 
Table 3-2 Example of imputation .......................................................................................................... 30 
Table 3-3 MRI endpoints & analyses ..................................................................................................... 32 
 35 
 37 
 39 
Table 4-1 AE date imputation ............................................................................................................... 44 
Table 4-2 Criteria for clinically notable abnormalities .......................................................................... 47 
Table 4-3 The lower limit of detections of laboratory parameters ....................................................... 48 
Table 4-4 Abnormal criteria .................................................................................................................. 49 
Table 4-5 Criteria for clinically notable vital signs ................................................................................. 51 
Table 4-6 Abnormality criteria for corrected QT interval ..................................................................... 53 
Table 12-1 Confidence Interval calculations ......................................................................................... 69 


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Protocol No. CFTY720D2312 
 
 
1 
Statistical methods planned in the protocol and 
determination of sample size 
Data will be analyzed by 
 statisticians and statistical programmers assigned to this study 
according to the data analysis section 9 of the study protocol and protocol amendments which is 
available in Appendix 16.1.1 of the CSR.  Important information is given in the following sections and 
details are provided, as applicable, in Appendix 16.1.9 of the CSR. 
2 
Statistical and analytical plans 
Unless otherwise stated, summary tables/figures/listings will be on all subjects included in the 
respective analysis set.  
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be presented.  
The contrast for between-treatment comparisons (ex. ARR, ARR-ratio) and corresponding p-values 
will be provided in section 16 SAS output tables. But between treatment comparison and 
corresponding p-value for the comparison between the two FTY doses (ex. ARR-ratio) will not be 
presented in the in-text and post-text tables. On in-text and post-text tables, the comparisons for 
FTY720 0.5 mg vs GA 20 mg, FTY720 0.25 mg vs GA 20 mg and the corresponding p-values will be 
displayed. In addition, the p-values generated from analysis models will be displayed up to 4 decimal 
places for reuse in publication as well as in CSR. 
The primary objective of the study is to demonstrate that at least one dose (tested hierarchically 0.5 
mg followed by 0.25 mg) of fingolimod is superior to glatiramer acetate 20 mg SC in reducing the ARR 
up to 12 months in subjects with relapsing-remitting MS. 
 
 
 
 
 
A general note on considering country or region in an efficacy analysis model: An adjustment for 
country or region will be considered in the initial model. If the initial model can not generate 
estimates with region as a factor, then country or region will be removed from the model for further 
specified analysis. 


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3 
Subjects and treatments, general rules and definitions  
3.1 
Analysis sets 
The following analysis sets will be used:  
• 
Randomized set (RS): consists of all subjects who are assigned randomization numbers. The 
subjects in this set are called randomized subjects. This set will be used to summarize subject 
disposition, demographic and baseline characteristics, and protocol deviation information. 
Subjects will be grouped according to randomized treatment. 
• 
Full-analysis set (FAS): Consists of all subjects who are randomly assigned and take at least 1 
dose of study drug. Following the intent-to-treat principle, subjects will be grouped according to 
the assigned treatment at randomization. Efficacy analyses will be performed on the full-analysis 
set unless otherwise notified. 
• 
Per-protocol set (PPS): Consists of all subjects in the FAS who do not have any major protocol 
deviations that could confound the interpretation of analyses conducted on the FAS. Major 
protocol deviations will be determined according to the predefined protocol deviation criteria 
before treatment unblinding. Any efficacy data after study drug discontinuation will be excluded. 
The per-protocol set will only be used for the supportive analyses of the primary efficacy 
variable. 
• 
Safety set (SS): Consists of all subjects in the FAS who take at least 1 dose of study drug. Subjects 
will be analyzed according to the treatment they have actually taken. Safety and tolerability 
analyses will be performed on the safety set unless otherwise specified. 
• 
Follow-up set (FUS): The follow-up set consists of all subjects in the safety set who have follow-
up visit data or who have at least 1 safety assessment (AEs, laboratory test, vital sign 
measurement, PFTs or ophthalmology assessments) 46 days or more than 46 days after study 
drug discontinuation. Subjects will be grouped in the same way as previously described for the 
analysis on the safety set. Only the safety follow-up data analysis will be performed on the 
follow-up set. 
3.2 
Subject disposition 
Subject disposition will be summarized on the randomized set. The number and proportion of 
subjects who complete the study or discontinue the study prematurely along with the reason for 
discontinuation will be presented. The number and proportion of subjects who discontinue the study 
drug prematurely along with the reason for study drug discontinuation will be summarized and 
presented separately. A listing will also be provided with treatment group and subject number.  
 
Additionally two types of subject discontinuation listings will be provided per FDA request.  


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• 
Discontinuation of study drug after which patients are still allowed to continue to have 
efficacy/safety assessment according to abbreviated schedule without receiving study drug 
treatment until the end of study.  
• 
Discontinuation from the study in which no further safety/efficacy will be assessed except for 
follow-up.   
Due to the non-specific nature of the HA communication, both types of listings are provided with the 
additional detail requested (under the heading “Relevant information related to reason”). 
Reasons for screen failure will be summarized for all screened subjects. 
3.3 
Protocol deviations 
Protocol deviations will be summarized by treatment group on the randomized set.  The major 
protocol deviations (severity codes of 0, 1, and 8) resulting in subjects’ exclusion from analysis sets 
are defined in study CFTY720D2312 VAP Module 3 – Protocol Deviation. Please refer to study VAP 
M3 for details.  
The analysis sets and severity codes used in the trial programming are listed in Table 1-1,  which 
includes the analysis set codes 1-5 and the severity codes  0, 1, 5, 8 and  49 for the double-blind 
treatment period.  
Table 1-1 The analysis sets and severity codes 
Analysis set codes 
Severity Codes 
1 = Randomized set 
2 = Full analysis set 
3 = Per protocol set 
4 = Safety set 
5 = Follow-up set 
0 = Exclude subject from all efficacy analyses 
1 = Exclude subject from per-protocol analysis 
5 = Exclude subject from all safety analyses 
8 = Exclude subject from all analyses 
49 = Include subject in all analyses 
 
Deviation Severity Codes 
Analysis set (code) 
0 
1 
5 
8 
49 
     Randomized set (1) 
Yes 
Yes 
Yes 
Yes 
Yes 
     Full analysis set (2) 
No 
Yes 
Yes 
No 
Yes 
     Per protocol set (3) 
No 
No 
Yes  
No 
Yes 
     Safety set (4) 
Yes 
Yes 
No 
No 
Yes 
     Follow-up  set (5) 
Yes 
Yes 
No 
No 
Yes 
      
 
 
 
 
 
Note: 'Yes’ means include in the analysis set, ‘No’ means exclude from the analysis set. 
Additionally, unblinding per protocol due to safety reasons may occur during the study. If a 
subject’s treatment code is revealed to any observer or study center personnel who are 


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Protocol No. CFTY720D2312 
 
intended to be blinded during the evaluation period (as marked on the study completion CRF 
page), that subject will also be excluded from the per-protocol set. A list of those subjects will 
also be presented. 
Note: Novartis study team discussed and agreed that FTYD2312 should follow the old PD 
process due to the following key reasons: 
• FTYD2312 Data Management has been following the old process and data is collected on 
paper forms  
• The dates of the FTYD2312 Initial SAP (10/18/2011) and the 1st amendment of the SAP 
(6/3/2014) are prior to the roll-out date specified for the new PD Process (3/28/2016 
3.4 
Background and demographic characteristics 
Background and demographic characteristics include age at screening derived from date of birth and 
the screening assessment date, gender, race, and ethnicity collected on the demography CRF, height, 
and body weight recorded at baseline on the vital signs CRF, and body mass index (BMI) calculated as 
(body weight in kilograms) / (height in meters)2. 
These variables recorded at baseline will be summarized on the randomized set by presenting 
frequency distributions (for categorical variables) or summary statistics (for continuous variables). 
It is anticipated that in some cases baseline body weight may be missing. For baseline characteristics, 
the algorithm to derive baseline body weight is as follows: it is the last assessment of any evaluations 
done up to the time of first dose; if there is no such assessment, it will be the first assessment of any 
evaluations done after first dose. In the situation that  baseline and post-baseline weight summaries 
are part of the vital sign summaries, missing body weights will be treated as missing.  
In the computation of creatinine clearance using the Cockcroft-Gault formula, the last assessment of 
body weight made on or prior to the day when the subject takes the laboratory test will be used. 
Table 1-1a The derivation formula for creatinine clearance 
Creatinine clearance [mL/min] using Cockroft-
Gault formula (Cockcroft and Gault, 1976) 
 
 
= (140 – A) × W  / (72 × C) × G 
    Where 
A is age [years] 
W is body weight [kg] 
C is the serum concentration of creatinine 
[mg/dL] 
G is a gender: G=1 for males and G=0.85 for 
females. 


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Creatinine clearance [mL/min] using 
abbreviated MDRD formula (Levey et al, 2000) 
 
 
= 186.3 × C - 1.154 × A - 0.203 × E × S 
     Where 
C is the serum concentration of creatinine 
[mg/dL], 
A is age [years], 
E is ethnicity: E=1.212 if patient is black, else 
E=1, 
S is gender: S=0.742 (if patient is female), else 
S=1. 
 
3.5 
MS disease and medical history 
Any condition entered on the relevant medical history/current medical conditions CRF will be coded 
using the MedDRA dictionary. 
Relevant medical history/current medical condition, pulmonary history, MS disease history and 
duration of the disease, MS related eye history, MS medication history (including history of disease-
modifying drugs and other drugs), MS symptoms and number of relapses  in the past 2 years before 
study enrolment, and MS disease baseline characteristics including baseline MRI assessments and 
baseline EDSS will all be summarized on the randomized set.  
The relevant medical history and continuing medical conditions will be summarized by primary 
system organ class (SOC) and preferred term (PT). MS medical history of other drugs will be 
summarized by preferred term. 
For the MS disease history summary, duration of MS since diagnosis (years) will be derived as 
follows:  (the first dose date – the MS diagnosis date + 1)/365.25; duration of MS since first symptom 
(years) will be derived as follows: (the first dose date – the first MS symptom date + 1)/365.25; time 
since the onset of the most recent relapse (months) will be derived as follows: (the first dose date – 
the most recent relapse onset date + 1)/30. 
For the MS diagnosis date and the first MS symptom date, the following rule will be used when 
imputing a partial date (complete missing date will not be imputed):  
a) Only year yyyy is available. The imputed date will be 1-July-yyyy.  
b) Both year yyyy and month mmm are available. The imputed date will be 15-mmm-yyyy.  
For the most recent relapse onset date, the following rule will be used when imputing a partial date: 
a) Only year yyyy is available. The imputed date will be 1-Jan-yyyy.  
b) Both year yyyy and month mmm are available. The imputed date will be 01-mmm-yyyy.  


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For the MS medication history of disease-modifying drugs (DMDs), the treatment naïve subjects are 
defined as those who never took the approved MS medications or other MS treatment as specified in 
Table 1-2. 
Any subject previously treated with any MS therapies (marked as ‘Yes’ on “Previous MS treatment” 
CRF page) will not be considered treatment naïve. When displaying these drugs in the tables, the 
names specified in Table 1-2 will be used. 
Table 1-2 Display of drug names 
Drug name collected in database 
Drug name to be used in display 
Azasan® , Azimune, Azoprin, Azathine, Azoran, 
Imuzat, Zymurine, Imuran® 
Azathioprine 
Interferon beta-1a (Avonex®)  
Interferon beta-1a i.m. 
Interferon beta-1a (Rebif®)  
Interferon beta-1a s.c. 
Interferon beta-1b 
(Betaferon®/Betaseron®/Extavia®) 
Interferon beta-1b s.c. 
Glatiramer acetate (Copaxone®)  
Glatiramer acetate 
Natalizumab (Tysabri®/Antegren®)  
Natalizumab 
Rheumatrex®, Trexall®, Amethopterin, MTX 
Methotrexate 
Aubagio 
Teriflunomide 
Tecfidera 
Dimethyl fumarate (BG12) 
New approved drugs 
 
Other  
Other MS medications 
3.6 
Study medication 
Duration of exposure to randomized study medication will be summarized on the safety set by 
presenting the number (and percentage) of subjects being exposed for a minimum duration of time 
as specified in Table 1-3 Duration in terms of number of days as shown in the second column will be 
used in the summary for the display of duration. 
Duration of exposure is the number of days on study drug during the core study phase. The 
days when the subject does not take the study drug will be excluded. That is, duration of 
exposure will exclude periods of temporary interruption of study medication. Note: for the last 
dosing interval entered on the Dosage Administration Record CRF, if the dosing end date is 
partial date, impute the first day for missing day and January for missing month.   
Summary statistics of duration of exposure to study medication will also be presented, which 
included mean, SD, minimum, maximum, etc. 
For each treatment group, the patient-years, which will be calculated as (the sum of the number of 
days on study drug for all subjects in the group)/365.25, will also be presented. 


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Table 1-3 Definitions of time-intervals used to summarize exposure to study 
medication 
Duration 
Duration in terms of number of days 
Any Exposure  
≥1 day 
≥1 week 
≥7 days 
≥2 weeks 
≥14 days 
≥1 month 
≥30 days 
≥2 months 
≥60 days 
≥3 months 
≥90 days 
≥6 months 
≥180 days 
≥9 months 
≥270 days 
≥12 months 
≥360 days 
3.7 
Concomitant medication/therapy 
Free-text records on the Concomitant medications / significant non-drug therapies CRF will be coded 
using NOVDTD drug dictionary (Novartis updated version of WHODRUG).  
All medications recorded on the Concomitant medications / significant non-drug therapies form will 
be classed as prior or concomitant medications and summarized separately, in alphabetical order, by 
ATC class and preferred term. Tables will show number of subjects (receiving at least one drug of a 
particular ATC class and at least one drug in a particular preferred term) and percentages.  
Prior medications will be drugs taken prior to first dose of randomized study medication but not at 
any time after baseline; any medication given at least once between the day of first dose of 
randomized study medication and the last day of randomized study medication will be a concomitant 
medication. Concurrent medications could start before first dose of randomized study medication 
but continue through after the first dose of randomized study medication. Any medication started 
after the discontinuation of randomized study medication will not be considered concomitant 
medication. Medications will be categorized into one (and only one) of above classes based on 
imputed start and end dates. 
Concomitant medication (CMD) date imputation will be based on a comparison between the partial 
CMD start date and the treatment start date and if necessary, on the CMD type as well which is also 
recorded on the CRF (i.e., the variable CMDTYP1C with 3 possible outcomes: prior medication, 
concomitant medication, or prior/concomitant medication). Date comparisons will be based on the 
year and month values only (i.e., day values will be ignored) as shown in Table 1-4. 
1. If the CMD start date year value is missing, the following imputation rules will apply.   


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a. If the CMD type is either prior medication or prior/concomitant medication, the CMD 
start date will be imputed as the date one day before the treatment start date.   
b. If the CMD type is concomitant medication or missing, the CMD start date will be 
imputed as the date one day after the treatment start date.   
2. If the CMD start date year value is less than the treatment start date year value, then the CMD 
must have started before treatment.   
a. If the CMD month is missing, the CMD start date will be imputed as the mid year date 
(01JulYYYY). 
b. If the CMD month is not missing, the CMD start date will be imputed as the mid month 
date (15MONYYYY). 
3. If the CMD start date year value is greater than the treatment start date year value, then the 
CMD must have started after treatment. 
a. If the CMD month is missing, the CMD start date will be imputed as the year start date 
(01JanYYYY). 
b. If the CMD month is not missing, the CMD start date will be imputed as the month start 
date (01MONYYYY). 
4. If the CMD start date year value is equal to the treatment start date year value, then the month 
values will be compared as follows. 
a. If the CMD month is either missing or equal to the treatment start month, the following 
imputation rules will apply. 
i. 
If the CMD type is either prior medication or prior/concomitant medication, the 
CMD start date will be imputed as the date one day before the treatment start 
date. 
ii. 
If the CMD type is concomitant medication or missing, the CMD start date will be 
imputed as the date one day after the treatment start date. 
b. If the CMD month is less than the treatment start month, the CMD start date will be 
imputed as the mid month date (15MONYYYY). 
c. If the CMD month is greater than the treatment start month, the CMD start date will be 
imputed as the start month date (01MONYYYY). 
 
Table 1-4 CMD date imputation 
 
 


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3.8 
Visit windows and cutoffs for efficacy and safety analyses 
This section defines the data cutoffs within which data will be included in the analysis and time points 
for which data will be summarized. 
Due to the study design, both data collected at Month 12 visit as end of the treatment (EOT) (also as 
end of study (EOS) visit) and data collected at the study drug discontinuation visit as EOT will be 
recorded in the CRF at EOT (corresponding to Visit 777 in the database). For subjects who discontinue 
study drug early but continue through the study per abbreviated schedule, the EOT visit and EOS visit 
may be different, in which case data collected at the EOS visit will be recorded in the CRF at study 
completion visit (corresponding to Visit 778 in the database). For subjects whose EOT visit and EOS 
visit are the same, data will be collected only once at the EOT visit. Therefore, there will be no 
corresponding Visit 778 in the database for these subjects. In the subject completion (CMP) data set, 
data collected from the study drug discontinuation CRF (Visit 777) and study completion CRF (Visit 
778) will be differentiated by visit number although there is no actual study visit corresponding to 
Visit 778 for subjects whose EOT visit and EOS visit are the same. .  
3.8.1 
Study Day 1 and other study days 
The first day of administration of randomized study medication (i.e., the first dose date of the study 
drug) is defined as Study Day 1 or Day 1.  
All other study days will be labeled relative to Day 1.  For event dates on or after Day 1, study day for 
an event date is calculated as (event date – first dose date +1), which could be Day 1, Day 2, Day 3, 
etc.  For event dates before Day 1, study day for an event date is calculated as (event date – first dose 
date), which could be Day -1, Day -2, etc., referring to one day, two days, etc., before Day 1, 
respectively. Duration of an event will be calculated as (event end date – event start date + 1). 
One month is defined as 30 days. 


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3.8.2 
Screening/Baseline 
Screening refers to any procedures (e.g. checking inclusion and exclusion criteria) performed prior to 
first dose date. Subject informed consent is generally obtained prior to any assessment. Any 
assessment obtained prior to first dose date will be called screening assessment. 
In general, a baseline value refers to the last measurement made prior to the administration of the 
first dose of the study drug. Assessments made on Day 1 may occur before or after the first dose. The 
following rules will be applied to determine which record is the last measurement prior to the first 
dose (i.e., the baseline value). 
• 
Consider all records with an assessment date before or on the first dose date. Baseline is the 
last record after sorting all above records with respect to assessment date, visit and repeat 
visit number. 
• 
Some data specific rules for determining baseline will be applied as described below or in 
data specific sections if applicable. 
For vital signs, the average of the 3 readings from Day 1 pre-dose at each position (sitting, supine or 
standing) will be used as baseline for that position. If unavailable, the last available average value 
from visits (including unscheduled) before the first dose will be used. For sitting pulse the last 
available single value before the first dose will be used as baseline. 
For ECG, the Day 1 pre-dose value will be used as baseline. If unavailable, the last available (including 
unscheduled) value before the first dose will be used.  
The pre-dose time point is the record at scheduled time point 0 (i.e., variable STM2N equals 0). 
3.8.3 
Nominal visits and visit windows 
3.8.3.1 
Nominal visits 
For EDSS, 
, PRO variables (except C-SSRS), dermatology exam, MRI and OCT, the nominal 
visit will be used in the by-visit summaries. Data from unscheduled visits for these assessments will 
not be summarized unless otherwise specified.  
The end of treatment or early discontinuation visit (Visit 777) will be the nominal 12 month visit for 
subjects who complete the study on study drug. For subjects who discontinue the study drug 
prematurely, the end of treatment or early discontinuation visit (Visit 777),  the follow-up visit (Visit 
501) and the end of study visit (Visit 778) which are not timepoint specific visits will be remapped 
based on the following rules: 
• 
If these visits fall into a specific visit window and the corresponding scheduled visit is missing, 
then these visits will be remapped to be that scheduled visit. The visit windows are defined as 
within 5 days of the scheduled visit (+/-5 days from the target day at each visit). 


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• 
If these visits fall into a specific visit window and the corresponding scheduled visit (e.g., Visit X) is 
not missing, then these visits will be assigned a visit number with a decimal place where the visit 
number depends on whether the corresponding scheduled visit occurs before (e.g., Visit X.1 or 
Visit X.2 if Visit X.1 already exist etc.) or after these visits (e.g., Visit X-1.1 or Visit X-1.2 if Visit X-
1.1 already exist etc.) 
• 
If these visits do not fall into a specific visit window but fall in between 2 consecutive  scheduled 
visit windows (e.g., between visit windows of Visit X and Visit X+1), then these visits will be 
assigned a visit number with a decimal place (e.g., Visit X.1 or Visit X.2 if Visit X.1 already exist 
etc.).  
The remapped visits (e.g., Visit X) will be treated as nominal visits in the by-visit summaries.  
For dermatology exam and OCT the above visits (Visit 777, Visit 501 and Visit 778) will not be 
remapped. 
3.8.3.2 
Visits windows 
For data not listed in Nominal visit Section 3.8.3.1, visit windows will be defined and used in the by-
visit summaries. Visit windows will only be defined for post-baseline visits and applied to post-
baseline data (including both scheduled and unscheduled visits). Based on the study assessment 
schedule (see Table 6-1 and Table 6-2 in the study protocol), visit windows are defined by a set of 
days around each nominal visit target day. For any assessment, there are at most 6 scheduled visits 
around which visit windows will be created: Months 1, 3, 6, 9, 12 and Follow-up.  
Visit windows for vital signs, lab, ophthalmologic examination (excluding OCT), pulmonary function 
tests (PFTs), ECG, and C-SSRS are provided in Table 2-1 to Table 2-5. These visit windows will not be 
applied to any data related to the first dose or second dose or restart dose monitoring which will be 
summarized separately. 
When visit windows are used, all post-baseline visits will be re-aligned, i.e., they will be mapped into 
one of the visit windows. E.g., if a subject’s Month 1 visit is delayed and occurs on Day 47, then it will 
be re-aligned to visit window Month 2. As a result, it is possible that several assessments may fall into 
one particular visit window. Statistical approaches to handle multiple visits in a given visit window 
are described in Multiple assessments within visit windows Section 3.8.6. 
Table 2-1 Visit windows for vital signs and laboratory values 
Visit 
Start day 
Target Day 
End day 
Month 1 
1 
30 
60 
Month 3 
61 
90 
135 
Month 6 
136 
180 
225 
Month 9 
226 
270 
315 
Month 12 
316 
360 
last dose date day +45 


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Follow-up 
Last dose date day + 
46 
450 
 
Table 2-2 Visit windows for PFTs 
Visit 
Start day 
Target Day 
End day 
Month 6 
1 
180 
270 
Month 12 
271 
360 
last dose date day +45 
Follow-up 
Last dose date day + 
46 
450 
 
Table 2-3 Visit windows for ophthalmologic examination (excluding OCT) 
Visit 
Start day 
Target Day 
End day 
Month 3 
1 
90 
135 
Month 6 
136 
180 
270 
Month 12 
271 
360 
last dose date day +45 
Follow-up 
Last dose date day + 
46 
450 
 
Table 2-4 Visit windows for ECG 
Visit 
Start day 
Target Day 
End day 
Month 12 
1 
360 
last dose date day +45 
Follow-up 
Last dose date day + 
46 
450 
 
 
Table 2-5 Visit windows for C-SSRS 
Visit 
Start day 
Target Day 
End day 
Screening 
-45 
NA 
-1 
Baseline 
1 
1 
1 
Month 1 
2 
30 
60 
Month 3 
61 
90 
135 
Month 6 
136 
180 
225 
Month 9 
226 
270 
315 
Month 12 
316 
360 
last dose date day +45 
Follow-up 
Last dose date day + 
46 
450 
 


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3.8.4 
Time points for first dose monitoring ECG and Vital signs 
For the first dose monitoring ECG, data will be summarized for the following time points: 
• 
Day 1 pre-dose: day 1 ECG value at 0 hour per time label 
• 
Day 1 post-dose (6 hours): day 1 ECG value at 6 hours per time label.  
• 
Day 1 post-dose (>6 hours): the mean of all day 1 ECG values after 6 hours per time label 
(including unscheduled values).  
Unscheduled ECG measured between the day 1 pre-dose and the 6 hours post-dose will not be 
summarized but reported in the data listing only. For the second dose monitoring ECG, data will be 
summarized similarly. 
For the first dose monitoring vital signs, data will be summarized for the following time points: 
• 
Day 1 pre-dose: day 1 vital sign value at 0 hour per time label 
• 
1 hour post-dose   
• 
2 hours post-dose  
• 
3 hours post-dose  
• 
4 hours post-dose  
• 
5 hours post-dose  
• 
6 hours post-dose  
The vital sign values at specified hours per time label post-dose will be used. Extended first dose 
monitoring after the 6 hours post-dose will not be summarized but reported in the data listing only. 
For the second dose or restart dose monitoring vital signs, data will be summarized similarly. 
3.8.5 
Safety data cutoff and visit windows for summaries on follow-up set 
For safety summaries on the safety set, only data which are within 45 days (5 times the half life of 
FTY720, 9 days) after the last dose of study drug will be considered.  
For safety summaries on the follow-up set, all data (including assessments or events more than 45 
days after the last dose of study drug) will be considered.  
The visit windows below will be used in summaries on the follow-up set.  
1) Last assessment on study drug  
2) Day 1 to 45 after study drug discontinuation  


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3) Month 3 (day 46 to 135) after study drug discontinuation 
4) Month 6 (day 136 to 270) after study drug discontinuation  
5) Month 12 (day 271 to 540) after study drug discontinuation 
For the visit window 1), last assessment on or before the last dose date will be used. For visit 
windows 2) to 5), assessments collected during the specified day intervals after the last dose date will 
be used. 
3.8.6 
Multiple assessments within visit windows 
For visit windows defined in Visit windows Section 3.8.3.2, multiple records may exist in one 
particular visit window. The following rules (unless otherwise specified) will be applied to obtain one 
value per subject per visit window which will be used in the by-visit summaries. 
• 
For quantitative variables (i.e., continuous variables for which summary statistics and change 
from baseline tables will be provided), the average of the multiple records will be used.  
• 
For qualitative variables (i.e., binary or nominal variables for which incidence rates and frequency 
distribution tables will be provided), the worst record will be used. It is noted that in the analyses 
performed, worst case is always well defined.   
Note that “Last assessment on study drug” is not like other visit windows but more like a single time 
point. The assessment to be summarized at that time point is the last on drug observation which is 
the last observation a subject has while he or she is on study drug. Therefore, the above multiple 
assessment rules do not apply.  
In addition, the multiple assessment rules do not apply to the first dose/second dose monitoring data 
and the restart dose monitoring data. 
For tables to display worst case scenario, such as shift tables, and on listings, multiple assessments 
will be used as they are and no average values will be taken. 
3.8.7 
Last dose day of randomized study medication 
The last dose date of the randomized study drug will be collected on three CRFs: 
1) The last date subject took study drug on the study completion CRF (CMP panel), 
2) The last date subject took study drug on the study drug discontinuation CRF (CMP panel),  
3) The last end date on the study drug administration record CRF (DAR panel). 
The last dose date recorded in the CMP panel will be used. If the last dose date in the CMP panel is 
partial date, impute the first day for missing day and January for missing month. If the last dose date 
in the CMP panel is completely missing, the last dose date recorded on the DAR panel will be used.  
 


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3.9 
Pooling of centers 
Total 6 countries participate in this study (Argentina, Brazil, Canada, Chile, Mexico and US) with 
majority of subjects from US. Region will be defined by pooling of centers as follows and will be used 
in the analysis as a factor. 
• 
Centers from Latin American countries (i.e. Argentina, Brazil, Chile, and Mexico) will be pooled as 
a region called Latin American region. 
• 
Centers from US/Canada will be pooled according to their geographic location and the number of 
subjects randomized as follows. 
1. Centers from US states of CA, WA, OR, NV, AZ, MT, UT and Canadian western 
provinces of British Columbia, Alberta, Saskatchewan, and Manitoba will be pooled 
as a region called West region. 
2. Centers from states of TX, CO, NM, KS, OK, MO will be pooled as a region called 
Southwest region. 
3. Centers from states of WI, IA, IL, MI, IN, OH, KY, WV will be pooled as a region called 
Midwest region. 
4. Centers from US states of NJ, PA, MD, DC, DE, VT, NH, MA, CT, NY and Canadian 
Eastern provinces of Quebec, Ontario and Nova Scotia will be pooled as a region 
called Northeast region. 
5. Centers from states of FL, TN, AL, GA, LA, VA, NC, SC, PR will be pooled as a region 
called Southeast region. 
 
The pooling of centers is performed so that there will be sufficient number of subjects in each region. 
If a statistical model stratified by region does not converge due to small number of subjects or small 
number of events in one or more regions, then regions will be further combined as needed. 
4 
Efficacy evaluation 
4.1 
Primary and key secondary efficacy variables 
4.1.1 
Primary efficacy variable 
The primary efficacy variable is the annualized relapse rate (ARR) which will be analyzed on both the 
full analysis set (primary analysis) and the per-protocol set (supportive analysis). The ARR can be 
calculated in two ways: 
1. Group level (aggregate ARR) 


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The ARR of a treatment group is calculated as the sum of the number of confirmed relapses of all 
subjects in the group divided by the sum of the number of days in study of all subjects in the group 
and multiplied by 365.25. 
The group level ARR is the primary efficacy variable. 
2. Subject level 
The ARR of an individual subject is calculated as the number of confirmed relapses divided by the 
number of days in study and multiplied by 365.25. The ARR of a treatment group is the mean of ARRs 
of all subjects in the group. 
4.1.2 
Key secondary efficacy variable 
Not applicable.  
4.1.3 
Time in study (years) for aggregate ARR  
Time in study is the number of days from the first study drug dose date to the study completion visit 
date or the last study drug dose date whichever occurs later. It will be calculated as:  
Time in study = Max (Study completion visit date, last study drug dose date) – first study drug 
dose date + 1 
Note that the study complete visit date is defined as follows:  
1. For subjects who completed study drug, or completed the abbreviated schedule of 
assessments after discontinuing the study drug prematurely, the study completion visit date 
is the Visit 7/Month 12 visit date.  
2. For subjects who discontinued study drug prematurely and did not complete the abbreviated 
schedule of assessments, the study completion visit date is the end of study (EOS) visit date. 
If a subject did not have an EOS visit date, then the last study visit date excluding follow-up 
visit will be used 
The time in study (years) will be calculated as the number of days in study/365.25.  
The confirmed relapses within this time period will be counted for each subject and will be used in 
the ARR computation.  
 
4.2 
Statistical methodology 
4.2.1 
Primary analysis 
The 2 doses of fingolimod will be tested hierarchically vs. glatiramer acetate in a step-down 
procedure. For each of the 2 fingolimod doses, the null hypothesis is that there is no difference in the 


N o v arti s  
C o nfi d e nti al  
P a g e 2 6  
R A P M o d ul e 3  
 
Pr ot o c ol N o. C F T Y 7 2 0 D 2 3 1 2  
 
A R Rs b et w e e n s u bj ects tr e at e d wit h fi n g oli m o d a n d t h os e tr e at e d wit h gl atir a m er ac et at e v ers us t h e 
alt er n ativ e  hy p ot h esis  t h at  t h er e  is  a  diff er e nc e  b et w e e n  t h e  2  tr e at m e nt  gr o u ps. I n  or d er  t o  
pr es erv e t h e T y p e I ex p eri m e nt -wis e err or r at e, th e n ull hy p ot h esis will b e r ej ect e d if t h e o bs erv e d p-
v al u e f or t h e b et w e e n -tr e at m e nt c o m p aris o n is l ess t h a n t h e si g nific a nc e l e v el as s p ecifi e d i n t h e 
m ulti plicity a dj ust m e nt pr oc e d ur e d escri b e d l at er i n t his s ecti o n.  
H 0 1: µ F T Y 0. 5  m g   = µ gl atir a m er ac et at e v ers us H A 1 : µ F T Y 0. 5  m g  ≠µ gl atir a m er ac et at e 
H 0 2: µ F T Y 0. 2 5  m g  = µ gl atir a m er ac et at e v ers us H A 2 : µ F T Y 0. 2 5  m g  ≠µ gl atir a m er ac et at e 
N o  f or m al  hy p ot h esis  will  b e  t est e d  b et w e e n  t h e  2  fi n g oli m o d  d os es b ec a us e  t h e  st u dy  is  n ot  
p o w er e d t o d et ect a diff er e nc e i n tr e at m e nt eff ect b et w e e n t h e  2 fi n g oli m o d d os es . 
T h e  hy p ot h es es  will  b e  t est e d  usi n g  a  n e g ativ e  bi n o mi al  r e gr essi o n  m o d el  wit h  l o g  li n k,  usi n g  
tr e at m e nt as m ai n eff ect, usi n g t h e n u m b er of r el a ps es i n t h e pr e vi o us y e ar b ef or e st u dy e nr oll m e nt, 
b as eli n e E D S S, a n d b as eli n e G d  + T 1 l esi o n c o u nt a n d c o u ntr y ( or r e gi o n) as c ov ari at es.  
I n t h e n e g ati v e bi n o mi al r e gr essi o n m o d el, t h e r es p o ns e v ari a bl e is t h e n u m b er of c o nfir m e d r el a ps es 
f or e ac h s u bj ect. T h e s u bj ect’s ti m e i n t h e st u dy ( n at ur al l o g of ti m e i n y e ars) is us e d as a n offs et 
v ari a bl e t o o bt ai n t h e A R R, a dj ust e d f or t h e v aryi n g l e n gt hs of s u bj ect’s ti m e i n t h e st u dy (ti m e i n 
y e ars). St u dy c e nt ers will  b e p o ol e d t o c o u ntr y or r e gi o n ( b as e d  o n  g e o gr a p hic al pr oxi mity a n d/ or  
k n o w n or ex p ect e d r e gi o n al diff er e nc es i n m e dic al c ar e) i n or d er t o mi ni miz e t h e i m p act of l o w  
e nr olli n g c e nt ers/c o u ntri es o n t h e a n alysis (s uc h as n o n -c o nv er g e nc e of t h e a n al ysis m o d el). D et ails 
of p o oli n g will b e pr ovi d e d i n t h e st atistic al a n alysis pl a n b ef or e d at a b as e l oc k . T h e S A S pr oc e d ur e 
G E N M O D ( or ot h er s oft w ar e wit h si mil ar f u ncti o n alit y) will b e us e d t o c o n d uct t h e a n al ysis.  
T h e tr e at m e nt eff ect of e ac h d os e of fi n g oli m o d v ers us gl atir a m er ac et at e will b e pr es e nt e d as a n 
A R R r ati o  (
/
F T Y  
G A
∧
∧
µ
µ
) wit h c orr es p o n di n g 9 5 % c o nfi d e nc e i nt er v al s a n d p v al u e s. I n a d diti o n, t h e 
r el ativ e r e d ucti o n i n A R R will b e pr es e nt e d as “ p erc e nt a g e c h a n g e,” c alc ul at e d as  (
/
F T Y  
G A
∧
∧
µ
µ
-1) . 
T h e pri m ar y a n al ysis wi ll b e c o n d uct e d o n t h e f ull a n al ysis s et. O nl y c o nfir m e d r el a ps es will b e 
c o u nt e d. 
4. 2. 1. 1  
M ulti pli cit y a dj u st m e nt f or st ati sti c al h y p ot h e si s t e sti n g  
T h e pri m ar y hy p ot h es es t ests will b e t est e d usi n g a hi er arc hic al st e p-d o w n pr oc e d ur e t o c o ntr ol t h e 
ex p eri m e nt -wis e err or r at e . 
T his st u dy is d esi g n e d t o c o m p ar e e ac h of 2 d os es of fi n g oli m o d t o gl atir a m er ac et at e b as e d o n A R R. 
T h er e ar e 2 hy p ot h es es b ei n g t est e d ( H 0 1, H 0 2).  
B ec a us e it is  hi g hl y  li k ely t h at t h e a p pr o v e d d os e of fi n g oli m o d ( 0. 5 m g) is m or e effic aci o us t h a n t h e 
l o w er d os e ( 0. 2 5 m g), t h e a p pr o v e d d os e of fi n g oli m o d  is i niti all y t est e d a g ai nst gl atir a m er ac et at e at 
a 2 -si d e d si g nific a nc e l ev el of 0. 0 5. O nl y if t his i niti al t est H 0 1 is r ej ect e d, will  t h e l o w d os e of 
fi n g oli m o d, b e t est e d a g ai nst gl atir a m er ac et at e als o at a 2 -si d e d si g nific a nc e l ev el of 0. 0 5.  


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Different scenarios of the anticipated treatment effect between fingolimod 0.5mg or 0.25mg versus 
glatiramer acetate have been evaluated based on the available data on fingolimod and the 
cumulative literature on glatiramer acetate. A 30% treatment benefit of fingolimod 0.5mg over 
glatiramer acetate could be anticipated on the basis of double-blind, 24-months, placebo-controlled 
studies of glatiramer acetate (Johnson et al, 2001) and fingolimod [Study CFTY720D2301] alone. 
However, more recent studies on glatiramer acetate, in a less active population, in a total of over 
3000 patients, suggest that the efficacy of glatiramer acetate on ARR and other endpoints is similar 
to that of IFN beta-1a SC (REGARDS) or IFN beta-1b SC (BEYOND). The observed relapse rates on 
glatiramer acetate were 0.29 in REGARDS and 0.34 in BEYOND, compared to 0.3 (INF beta-1a SC) and 
0.33 (INF beta-1b SC), respectively. In Study FTY720D2302, a double-blind 1-year study, fingolimod 
0.5 mg was directly compared to IFN beta-1a IM. The ARR (0.21) in patients treated with fingolimod 
0.5 mg was reduced by 52% compared to the ARR (0.43) in patients treated with INF beta-1a IM. 
Overall, the reduction in ARR in patients treated with fingolimod 0.5 mg compared to those treated 
with glatiramer acetate can be expected in the range of 30% to 50%. For the purpose of this study, a 
35% lower ARR in patients treated with fingolimod 0.5 mg (ARR=0.195) compared to those treated 
with glatiramer acetate (ARR=0.30) is assumed.  
Fingolimod 0.25 mg has never been tested in a clinical trial. Based on PK/PD modeling a 14% higher 
ARR in patients on fingolimod 0.25 mg compared to those on fingolimod 0.5 mg is anticipated. 
However, the uncertainty of this estimate is substantial. A 95% confidence interval from the PK/PD 
model for the ARR in patients on fingolimod 0.25 mg ranges from ARR=0.183 to ARR=0.303. For the 
purpose of this study, an ARR of 0.225 is assumed in patients treated with fingolimod 0.25 mg, which 
corresponds to an increase in ARR of approximately 15% compared to fingolimod 0.5 mg and a 
relative treatment effect of 25% compared to glatiramer acetate. 
4.2.1.2 
Supportive analyses of primary endpoint 
Supportive analyses will be performed for the primary endpoint as well as some variations of the 
primary endpoint (for sensitivity analysis purpose). All primary and supportive analyses are 
summarized below and in Table 3-1. The full analysis set will be used unless otherwise specified. 
Table 3-1 Primary efficacy endpoint, supportive endpoints & analyses 
Endpoint 
Analysis method 
 
Aggregate ARR 
(confirmed relapses 
only) (i.e., the 
primary efficacy 
variable) 
Negative binomial model (treatment 
as main effect, number of relapses in 
previous year, and baseline EDSS, 
baseline Gd + T1 lesion count as 
covariates) (region will be considered)  
Primary analysis 
Negative binomial model (treatment)  
Supportive analysis 1 
Negative binomial model (treatment 
Supportive analysis 2 


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as main effect, number of relapses in 
previous year, and baseline EDSS, 
baseline Gd + T1 lesion count as 
covariates) (region will be considered) 
on the full analysis set excluding 
subjects from site # 
 
Negative binomial model (treatment 
as main effect, number of relapses in 
previous year, and baseline EDSS, 
baseline Gd + T1 lesion count as 
covariates) (region will be considered) 
on the per-protocol set 
Supportive analysis 3 
Aggregate ARR 
(confirmed and 
unconfirmed 
relapses) 
Negative binomial model (treatment 
as main effect, number of relapses in 
previous year, and baseline EDSS, 
baseline Gd + T1 lesion count as 
covariates) (region will be considered)  
Supportive analysis 4 
Subject-level ARR 
(with imputation; 
confirmed relapses 
only) 
Rank ANCOVA (treatment as main 
effect, number of relapses in previous 
year, and baseline EDSS, baseline 
Gd + T1 lesion count as covariates) 
(region will be considered)  
Supportive analysis 5 
Aggregate ARR 
(confirmed relapses 
only and time in 
study truncated at 
367 days) 
Negative binomial model (treatment 
as main effect, number of relapses in 
previous year, and baseline EDSS, 
baseline Gd + T1 lesion count as 
covariates) (region will be considered)  
Supportive analysis 6 
Aggregate ARR 
(confirmed relapses 
derived by EDSS) 
Negative binomial model (treatment 
as main effect, number of relapses in 
previous year, and baseline EDSS, 
baseline Gd + T1 lesion count as 
covariates) (region will be considered)  
Supportive analysis 7 
1) For the primary endpoint, a supportive analysis will be performed using a negative binomial 
regression model adjusted for treatment group only. 
2) For the primary endpoint, a supportive analysis will be performed using the same negative 
binomial model as it is in the primary analysis but based on the full analysis set excluding all subjects 
from the site # 
. Subjects in site #
 were mismanaged by the primary investigator at this site. 
3) For the primary endpoint, a supportive analysis will be performed using the same negative 
binomial model as it is in the primary analysis but on the per-protocol set. Relapses that start after 


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study drug discontinuation will be excluded and log (time on study drug in years) rather than log 
(time in study in years) will be used as the offset variable in the negative binomial model with log 
link. The number of days on study drug is calculated as (the last study drug dose date – 1st study drug 
dose date +1) which will be used. This is an efficacy analysis of on-treatment data for subjects 
without major protocol deviations. 
4) Analyses described in the primary analysis section will be repeated for the ARR counting all 
relapses (including both confirmed and unconfirmed relapses). 
5) For the subject level ARR with imputation, a supportive analysis will be performed using Rank 
Analysis of Covariance (ANCOVA) with treatment group as main effect, number of relapses in the 
previous year before study enrollment, baseline EDSS, and baseline Gd + lesion count as covariates 
[Stokes (2000)]. An adjustment for country or region will be considered. For subjects who do not 
complete the treatment phase, relapses will be imputed (see Handling dropouts in ARR calculations 
Section). Additionally for subject-level ARR without imputation, summaries by treatment group will 
be presented. 
6) Analyses described in the primary analysis sections will be repeated for the confirmed relapses but 
the calculation for time in study is different. For this supportive analysis the time in study is the 
number of days from the first study drug dose date to the study completion visit date or the last 
study drug dose date whichever occurs later. If more than 367 (=12*30+7) days is obtained, then it 
will be cutoff to be 367 days which corresponds to 12 months plus a 7-day window. If the study 
completion visit date is not available, the latest study visit date will be used instead. The time in 
study (years) will be calculated as the number of days in study/365.25. The confirmed relapses within 
this time period will be counted for each subject and will be used in the ARR computation.  
7) Analyses described in the primary analysis sections will be repeated for the confirmed relapses 
where confirmation is derived based on EDSS/FS scores, not on the MS Relapses CRF.   For each 
relapse reported on the MS Relapses CRF the confirmation status is derived as the following: 
• 
If no EDSS is performed between start and end dates of the relapse, then the relapse is 
“unconfirmed” ; 
• 
If an EDSS is performed between start and end dates of the relapse, then compare the 
EDSS/FS scores to the last available EDSS excluding EDSS recorded during the previous 
MS relapses. If there is an increase of 0.5 in EDSS or one point on two different FS or 2 
points on one FS (all FS except bowel/bladder and Cerebral), the relapse is “confirmed”; 
otherwise it is “unconfirmed”.  
 
4.2.1.3 
Handling dropouts in ARR calculations 
1) Negative binomial regression model for aggregate ARR on the full analysis set: For subjects who 
discontinue the study prematurely, the number of relapses recorded in the study will be used 
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2) Negative binomial regression model for aggregate ARR on the per-protocol set: For subjects who 
discontinued the study drug prematurely, the number of relapses that start prior to or on the same 
day as the last dose date will be used and no imputation will be applied. 
3) Rank ANCOVA model for subject-level ARR with imputation on the full analysis set:  
For subjects who discontinue the study prematurely, the number of relapses per month for the 
months after discontinuation will be imputed by the corresponding monthly mean number of 
relapses of subjects across all treatment groups who has data of either 0 (no relapse) or 1 (one 
relapse) in that month. That is, for each month with completely missing data, the imputed number of 
relapses for the month is the average number of relapses for the corresponding month based on the 
available data from all subjects.  
Subjects may have data from part of the month during which they drop out. The number of relapses 
for that month will be the observed number of confirmed relapse (either 0 or 1) during that partial 
month. That is, if a subject drops out with one relapse during the dropout month, the subject will be 
counted as having one relapse for the entire month. If no relapse is observed in the dropout month, 
the subject is assumed to have no relapse for the entire month. This is accurate because a subject 
could only have at most one confirmed relapse in each month due to the definition of confirmed 
relapse in the protocol (Appearance of a new neurological abnormality or worsening of previously 
stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset 
of a preceding clinical demyelinating event).  
Only the relapse start date will be used to determine the month in which a relapse will be counted 
when calculating the number of relapses per month. 
The ARR of these subjects will be calculated based on the observed number of relapses before 
dropping out and the imputed number of relapses after dropping out. For example, suppose that the 
average number of relapses for each month based on all subjects contributing data to the month is as 
shown in Table 3-2. 
Table 3-2 Example of imputation 
Month 
Average # of relapses 
1 
0.20 
2 
0.19 
3 
0.18 
4 
0.17 
5 
0.16 
6 
0.15 
7 
0.14 


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8 
0.13 
9 
0.11 
10 
0.11 
11 
0.11 
12 
0.11 
 
If a subject discontinues the study on Day 130 (i.e., after 4 months and 10 days) after having one 
confirmed relapse, his number of relapses from Month 6 on will be imputed from the above table. 
His total number of relapses will be the sum of 1, 0.15, 0.14, 0.13, 0.11...0.11, which equals to 1.86. 
Note that the imputed portion of the number of relapses will be the same for subjects who drop out 
in the same month. 
The imputation will only apply to the dropout subjects up to 360 days (i.e., 12 months). After the 
imputation, the number of days in study for all dropout subjects is 360 days. For those who complete 
the study, the number of days in study will remain the same as defined in Time in study for aggregate 
ARR Section 4.1.3. 
4) Summary of subject-level ARR without imputation on the full analysis set: For subjects who 
discontinue the study prematurely, the number of relapses recorded in the study will be used and no 
imputation will be applied. 
4.2.1.4 
Missing MS relapse dates 
The following obvious corrections will be implemented by programming if the relapse partial start/or 
end date occurs where only day is missing. 
For an incomplete relapse start date where day is missing but month and year are available, the day 
will be entered as the first day of the month. In case the relapse partial start date is in the same 
month as the first study drug dose date, the relapse start date will be entered as the first study drug 
dose date. 
For an incomplete relapse end date where day is missing but month and year are available, the day 
will be entered as the last day of the month. In case the relapse partial end date is in the same month 
as the last visit date, the relapse end date will be entered as the last visit date. For a relapse is still 
ongoing at the last visit the relapse end date will be entered as the last visit date. 
4.2.2 
Analyses of secondary 
 variables  
Secondary efficacy variables will be analyzed on the full analysis set unless otherwise specified. For 
most analyses, all three pair-wise treatment comparisons (fingolimod 0.5 mg vs. glatiramer acetate, 
0.25 mg vs. glatiramer acetate, and 0.5 mg vs. 0.25 mg) will be provided even though no formal 
hypothesis will be tested between the 2 fingolimod doses. 


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4.2.2.1 
Magnetic resonance imaging (MRI) 
The analyses on MRI parameters will be performed on the full analysis set in the subset of subjects 
who have MRI scans done during the study.  For all MRI data, no visit mapping will be performed for 
any visit and all analyses will be performed according to the visit recorded in the MRI data set. 
The number and volume of Gd + lesion data obtained less than 30 days after use of steroid for 
treatment of relapses will be excluded from the analysis. 
Analyses of MRI variables are summarized in Table 3-3 below and details will be provided in the 
following section.  
Table 3-3 MRI endpoints & analyses 
Endpoint 
Analysis 
Brain atrophy - Percent brain volume 
change (PBVC) from baseline at Month 
12/end of treatment 
Rank ANCOVA (treatment, age, baseline 
normalized brain volume (NBV), and the number 
of relapses experienced in the previous year 
before study enrollment) (region will be 
considered) 
ANCOVA (treatment, age, baseline normalized 
brain volume, and the number of relapses 
experienced in the previous year before study 
enrollment) (region will be considered) 
ANCOVA (treatment, age, baseline Gd + T1 
lesion count, and baseline T2 lesion volume (in 
cc). (region will be considered) 
New/newly enlarged T2 lesion count 
(compared with baseline MRI scan) at 
Month 12/end of treatment 
Negative binomial (treatment, age, baseline T2 
lesion count, baseline Gd +  T1 lesion count, 
and the number of relapses experienced in the 
previous year before study enrollment) (region 
will be considered) 
Rank ANOVA (treatment, region) 
Proportion of subjects free of new/newly-
enlarged T2 lesions compared to baseline 
at Month 12/end of treatment 
Logistic regression (treatment, age, baseline T2 
lesion count, baseline Gd + T1 lesion count, and 
the number of relapses experienced in the 
previous year before study enrollment) (region 
will be considered) 
Change (and % change) from Baseline in 
T2 lesion volume at Month 12/end of 
Rank ANCOVA (treatment, age, baseline T2 
lesion volume,  and the number of relapses 


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treatment 
experienced in the previous year before study 
enrollment) (region will be considered) 
Gd + T1 lesion count at Month 12/end of 
treatment 
Negative binomial (treatment, age, baseline T2 
lesion count, baseline Gd + T1 lesion count,  
and the number of relapses experienced in the 
previous year before study enrollment) (region 
will be considered) 
Proportion of subjects free of Gd + T1 
lesions at baseline, Month 12/end of 
treatment 
Logistic regression (treatment, age,  baseline Gd 
+ T1 lesion count, and the number of relapses 
experienced in the previous year before study 
enrollment) (region will be considered) 
Gd + T1 lesion volume at Month 12/end of 
treatment 
Rank ANCOVA (treatment, age, baseline Gd + 
T1 lesion volume, and the number of relapses 
experienced in the previous year before study 
enrollment) (region will be considered) 
Proportion of subjects free of new T1 
lesions compared to baseline at Month 
12/end of treatment 
Logistic regression (treatment, age, baseline T1  
lesion count, baseline Gd + T1 lesion count, and 
the number of relapses experienced in the 
previous year before study enrollment) (region 
will be considered) 
Change and % change from baseline in 
T1 lesion volume at Month 12/end of 
treatment 
Rank ANCOVA (treatment, age, baseline T1 
lesion volume, and the number of relapses 
experienced in the previous year before study 
enrollment) (region will be considered) 
Percent brain volume change (PBVC) 
from baseline at Month 12/end of 
treatment 
New/newly enlarged T2 lesion count at 
Month 12/end of study 
Gd + T1 lesion count at Month 12/end of 
treatment  
Proportion of subjects free of new/newly 
enlarged T2 lesions and proportion of 
subjects free of Td + T1 lesions at Month 
12/end of treatment  
Sensitivity analyses to repeat the same 
analyses descripted above, but exclude baseline 
assessments performed > 45 days before 
randomization and end of treatment 
assessments performed > 45 days after the last 
dose of study drug.  
Annualized rate of brain atrophy (ARBA) 
at Month 12/end of treatment 
Sensitivity analyses to adjust for study duration 
and MRI covariates: 
Rank ANCOVA (treatment, age, baseline NBV, 
baseline Gd + T1 lesion count, and baseline T2 


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lesion volume, and the number of relapses 
experienced in the previous year before study 
enrollment) (region was considered) 
ANCOVA (treatment, age, baseline NBV, 
baseline Gd + T1 lesion count, and baseline T2 
lesion volume, and the number of relapses 
experienced in the previous year before study 
enrollment (region was considered) 
The number of new or newly enlarging T2 lesions at Month 12/end of treatment and number of Gd-
enhancing T1 lesions at Month 12/end of treatment will be analyzed using a negative binomial 
regression model with log link, using treatment as main effect, age, baseline T2 lesion count, baseline 
Gd-enhancing T1 lesion count, and the number of relapses experienced in the previous year before 
study enrollment as covariates. An adjustment for region will be considered in the model. For the 
analysis of T2 lesions, an offset variable will be used in the negative binomial analysis to adjust for 
the time in years (since start of study drug). 
The proportion type variables will be analyzed using a logistic regression model with treatment as 
main effect, age, corresponding baseline value, baseline Gd-enhancing T1 lesion count, and the 
number of relapses experienced in the previous year before study enrollment as covariates. An 
adjustment for country or region will be considered in the model. 
The continuous variables (change, percent change, and total volume) will be analyzed using a rank 
ANCOVA model with treatment as main effect, adjusted for age, corresponding baseline value, and 
the number of relapses experienced in the previous year before study enrollment as covariates. An 
adjustment for country or region will be considered. ANCOVA analysis for the percent change in brain 
volume with the above variables as covariates will be considered as well. In addition, an ANCOVA 
model with treatment, baseline Gd + T1 lesion count and the T2 volume (in cc) will be performed. 
 
4.2.2.2 
Relapses  
All relapse-related analyses use confirmed relapses only, unless otherwise specified. 
 
 
 
 
 
 
 
 
 
 


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4.2.2.5 
EDSS Scores 
Summary statistics will be presented on the FAS for the observed EDSS scores by visit and treatment. 
The change from baseline to end of study in EDSS score will be summarized on the FAS as well. 


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7 
Health-related Quality of Life (QoL) 


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7.3 
TSQM (Version 1.4) 
Treatment Satisfaction Questionnaire for Medication (TSQM) was developed and validated as a 
general measure for treatment satisfaction. The TSQM version 1.4 modified will be used, which 
contains 14 items assessing the following 4 domains: Global Satisfaction, Effectiveness, Side Effects, 
and Convenience.  This patient reported outcome (PRO) must be completed prior to any other study 
visit assessments at the specified visits according to Table 6-1 assessment schedule in study protocol. 
Scores for the TSQM version 1.4 will be generated using the authors’ scoring algorithm. Missing data 
will be treated in accordance with the authors’ guidelines (Atkinson et al 2004) as follows:   
EFFECTIVENESS:  
 
Score = {[(sum of items 1-3) – 3] / 18} * 100 
If only one item is missing, Score = {[(sum of available items in 1-3) – 2] / 12} * 100 
SIDE EFFECTS:  
If Question 4 is answered “No” then Score = 100. 
Otherwise: 
Score = {[(sum of items 5-8) – 4] / 16} * 100 
If only one item is missing, Score = {[(sum of available items in 5-8) – 3] / 12} * 100 


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CONVENIENCE:  
Score = {[(sum of items 9-11) – 3] / 18} * 100 
If only one item is missing, Score = {[(sum of available items in 9-11) – 2] / 12} * 100 
GLOBAL SATISFACTION:  
 
Score = {[(sum of items 12-14) – 3] / 14} * 100 
If only one item is missing: 
Item 12 or 13 missing:  Score = {[(sum of available items in 12-14) – 2] / 10} * 100 
Item 14 missing:           Score = {[(sum of available items in 12-14) – 2] / 8} * 100 
The higher summary scores indicate better satisfaction with study drug.  
Scores for each scale at scheduled visits will be summarized by treatment group with n, mean SD, 
minimum, Q1, median, Q3, and maximum. The change from baseline score will be compared within 
treatment group by Wilcoxon signed-rank test (also known simply as the Wilcoxon sign test). 
8 
Safety evaluation 
Safety assessments include adverse events, infections, bradycardia events, laboratory tests, vital 
signs, ECG, pulmonary function tests (PFTs), ophthalmic examinations, and dermatology assessment. 
All safety data will be summarized on the safety set. Some safety data (AEs, vital signs, labs, PFTs, and 
ophthalmic evaluations) will also be summarized on the follow-up set. 
Unless otherwise specified, safety assessments more than 45 days after the study drug 
discontinuation will not be included in the summaries on the safety set but will be considered in the 
summaries on the follow-up set. The 45 days rule should be applied as follows: 
45 days after the last study drug dose date will be the cutoff for safety data to be included in the 
summaries. 
Adverse events starting/ending before the first dose date will be excluded from the adverse event 
summaries i.e. only treatment emergent AEs will be summarized by treatment.  
Details of the safety data summaries will be provided in the sections below. All safety data will also 
be presented in the listings. 


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8.1 
Adverse events 
8.1.1 
Adverse event date imputation 
To ensure that all reported AEs are summarized, a conservative approach will be taken to impute the 
AE date when a partial date is available. AE date imputation is based on a comparison of the partial 
AE start date to the treatment start date (Table 4-1).   
1. If the AE start date year value is missing, the AE start date will be imputed as the treatment start 
date. 
2. If the AE start date year value is less than the treatment start date year value, the AE must have 
started before treatment. The following imputation rules will apply. 
a. If the AE month is missing, the AE start date will be imputed as the mid year date 
(01JulYYYY). 
b. If the AE month is not missing, the AE start date will be imputed as the mid month date 
(15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, the AE must 
have started after treatment. The following imputation rules will apply. 
a. If the AE month is missing, the AE start date will be imputed as the year start date 
(01JanYYYY). 
b. If the AE month is not missing, the AE start date will be imputed as the month start date 
(01MONYYYY). 
4. If the AE start date year value is equal to the treatment start date year value, the month values 
will be compared as follows. 
a. If the AE month is missing or the AE month is equal to the treatment start month, the AE 
start date will be imputed as the date one day after treatment start date. 
b. If the AE month is less than the treatment start month, the AE start date will be imputed 
as the mid month date (15MONYYYY). 
c. If the AE month is greater than the treatment start month, the AE start date will be 
imputed as the start month date (01MONYYYY). 


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Table 4-1 AE date imputation 
MON
MISSING
(F)=TRTSTD
(F)=TRTSTD
(F)=TRTSTD
(F)=TRTSTD
Uncertain
Uncertain
Uncertain
Uncertain
( D ) = 01JULYYYY
( C )= 15MONYYYY
( C )= 15MONYYYY
( C )= 15MONYYYY
Before Treatment Start Before Treatment Start Before Treatment Start Before Treatment Start 
(B)=
TRTSTD+1
( C )= 15MONYYYY
(A)=
TRTSTD+1
(A)=
01MONYYYY
Uncertain
Before Treatment Start 
Uncertain
After Treatment Start 
(E)=
01JANYYYY
(A)=
01MONYYYY
(A)=
01MONYYYY
(A)=
01MONYYYY
After Treatment Start 
After Treatment Start 
After Treatment Start 
After Treatment Start 
Before Treatment Start 
After Treatment Start 
Uncertain
LEGEND:
(A)
(B)
(C)
(D)
(E)
(F)
01JULYYYY
15MONYYYY
MAX(01MONYYYY,TRTSTD+1)
TRTSTD+1
TRTSTD
Partial indicates date prior to Treatment Start Date
MON < CFM
MON = CFM
MON > CFM
Partial indicates date after Treatment Start Date
Partial insufficient to determine relationship to Treatment Start Date
01JANYYYY
 
8.1.2 
Adverse events  
In this section, the term adverse event (AE) will refer to any entry on the adverse events CRFs. All AEs 
including infections will be coded using the MedDRA dictionary. The MedDRA version 20.0 or higher 
will be used depending when the study is completed. 
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of subjects having any AE by primary system organ class and preferred term. SAEs, death, 
drug-related AEs, the AEs leading to premature discontinuation of study drug, AEs requiring study-
drug dose adjustment or interruption and AEs requiring additional therapy will be presented in a 
similar format as AEs. Notable events will include death, nonfatal SAEs (including infections), and AEs 
(including infections) leading to study drug discontinuation. AEs that fulfill the risk search terms 
(defined in the case retrieval sheet) with RMP risk will be summarized by risk name and lower level 
terms. 


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SAEs include death and non-fatal SAEs. All SAEs starting after the first dose date, including those 
starting more than 45 days after study drug discontinuation, will be included in the summaries on the 
safety set. 
Additionally, occurrence rates of AEs, i.e. occurrence of AEs per 100 patient year by primary organ 
class and preferred term will be summarized. The occurrence rate of an event is calculated as the 
number (n) of all such events that patients experience divided by the patient years (Ny), where 
patient years are calculated as the sum of the number of days on study drug of all patients divided by 
365.25. The occurrence of AEs per 100 patient years, which is calculated as n/Ny*100, will be 
presented.  
AE summaries on the follow-up set will be conducted for the following time periods defined by days 
relative to study drug discontinuation: days 1 to 45 after study drug discontinuation, day 46 or later 
after study drug discontinuation.  
8.1.2.1 
Occurrence of SAEs and NSAEs (non-serious AEs) 
 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-treatment 
adverse events which are not serious adverse events with an incidence greater than X% and on on-
treatment serious adverse events and SAE suspected to be related to study treatment will be 
provided by system organ class and preferred term on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, seriousness 
and severity) occurred with the same SOC and PT: 
• 
a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• 
more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study treatment / 
non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at least one SAE is 
occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.  
 
8.1.3 
Data summaries for AEs 
Summaries on the safety set by treatment group include: 


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• 
Incidence of AEs by SOC and PT  
• 
Incidence of AEs that fulfill the risk search terms with RMP risk by risk name and level terms 
• 
Incidence of AEs by SOC and PT and severity 
• 
Incidence of deaths by SOC and PT 
• 
Incidence of SAE by SOC and PT 
• 
Incidence of SAEs that fulfill the risk search terms with RMP risk by risk name and level terms 
• 
Incidence of AEs leading to study drug discontinuation by SOC and PT  
• 
Incidence of AEs requiring study-drug dose adjustment or interruption by SOC and PT 
• 
Incidence of AEs requiring additional therapy by SOC and PT 
• 
Incidence of most frequent (>=1% for any group) AEs by PT  
• 
Incidence of AEs related to study drug by SOC and PT 
• 
Occurrence of AEs per 100 patient-years by SOC and PT 
• 
Occurrence of SAEs by SOC and PT 
• 
Occurrence of NSAEs by SOC and PT 
 
Summaries on the follow-up set by treatment group include: 
• 
Incidence of AEs by SOC and PT (days 1 – 45 after study drug discontinuation, and more than 
45 days after study drug discontinuation) 
8.2 
Laboratory data  
8.2.1 
SI Units 
Data summaries will be provided in SI units. The standard conversion tool (UNITCONV) will be used to 
convert all values in different units to SI units. 
8.2.2 
Clinically notable criteria 
Clinically notable criteria are summarized in Table 4-2. 
 
All applicable post-baseline laboratory results will be checked against the respective notable criteria. 
For a particular notable criterion, a subject will be counted in the notable abnormal category as long 
as one of the results meets the criterion. Note that a subject can be counted in both low and high 
abnormal categories.  


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For some laboratory parameters (as listed in Table 4-3), subjects may have a character value of “<x.x” 
or “<x” instead of the actual numeric value which are below the lower limit of detections (LLOD). The 
50% of the LLOD rule will be applied to transform a character value into a numerical value as 
specified in Table 4-3. This rule will be applied to all applicable lab values prior to checking against 
the notable criteria as well as computation of any statistics. 
For the laboratory parameters listed in Table 4-4, results will be summarized based on the abnormal 
criteria which are defined by pre-specified level of abnormality in terms of either LLN or ULN as listed 
in Table 4-4.  
In addition, the patients meeting modified Hy’s Law will be included in the summary of newly 
occurring or worsening post-baseline liver function test abnormalities. The modified Hy’s Law 
biochemical criteria is defined as at least one of (ALT or AST > 3 x ULN) and (total bilirubin >=2 x ULN) 
and (alkaline phosphatase < 2 x ULN) at a same visit. 
Table 4-2 Criteria for clinically notable abnormalities 
Laboratory Variable 
Standard Units 
SI Units 
LIVER FUNCTION AND RELATED VARIABLES 
SGOT (AST) 
> 82 U/L 
> 82 U/L 
SGPT (ALT) 
> 90 U/L 
> 90 U/L 
Gamma glutamyl transferase (GGT) 
(U/L) 
> 130 U/L 
> 130 U/L 
Bilirubin (total) 
≥ 2.0 mg/dL 
≥ 34.2 µmol/L 
Alkaline phosphatase, serum 
> 280 U/L 
> 280 U/L 
RENAL FUNCTION / METABOLIC AND ELECTROLYTE VARIABLES 
Glucose 
≥ 200 mg/dL 
≥ 11.11 mmol/L 
Creatinine 
≥ 2.0 mg/dL 
≥ 176 umol/L 
Amylase 
≥ 300 U/L 
≥ 300 U/L 
Cholesterol (total) 
≥ 240 mg/dL 
≥ 6.21 mmol/L 
Triglycerides 
≥ 300 mg/dL 
≥ 3.39 mmol/L 
BUN 
≤ 2 mg/dL 
≥ 30 mg/dL 
≤ 0.7 mmol/L 
≥ 10.7 mmol/L 
Sodium 
< 125 mEq/L 
> 154 mEq/L 
< 125 mmol/L 
> 154 mmol/L 
Chloride 
≤ 85 mEq/L 
≥ 119 mEq/L 
≤ 85 mmol/L 
≥ 119 mmol/L 
Potassium 
≤ 3.0 mEq/L 
≥ 6.0 mEq/L 
≤ 3.0 mmol/L 
≥ 6.0 mmol/L 
Magnesium 
≤ 1.0 mg/dL 
≤ 0.40 mmol/L  


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≥ 3.00 mg/dL 
≥ 1.23  mmol/L 
Calcium 
≤ 7.5 mg/dL 
≥ 11.6 mg/dL 
≤ 1.87 mmol/L 
≥ 2.89 mmol/L 
Phosphate 
≤ 2.0 mg/dL 
≥ 5.3 mg/dL 
≤ 0.65 mmol/L 
≥ 1.71 mmol/L 
HEMATOLOGY VARIABLES 
Haemoglobin 
≤ 10.0 g/dL 
≤ 100 g/L  
Platelets (Thrombocytes)  
 
<labeled as Platelet count (direct) in 
database>  
≤ 100 k/mm3 
≥ 600 k/mm3 
≤ 100 x 109/L 
≥ 600 x 109/L 
Leukocytes (WBCs)  
 
<labeled as WBC (total) in database> 
≤ 2.0 k/mm3 
≥ 15 k/mm3 
≤ 2.0 x 109/L 
≥ 15 x 109/L 
HEMATOLOGY VARIABLES: DIFFERENTIAL 
Granulocytes (Poly, Neutrophils)  
 
<labeled as Neutrophils (Seg. + 
Bands)> 
                  ≤ 1,000 /mm3 
                ≥ 12000/mm3 
≤ 1 x 109/L 
≥ 12 x 109/L 
Lymphocytes 
 
< 200/mm3 
≥ 8000/mm3 
< 0.2 x 109/L 
≥ 8 x 109/L 
Red blood cells (RBCs)  
< 3,300,000/mm3 
> 6,800,000/mm3 
< 3.3 x 1012/L 
> 6.8 x 1012/L  
*“Americas” refers to North (Canada, US), Central, and South America.  It is applicable only to Canada and US in this study. 
 
Table 4-3 The lower limit of detections of laboratory parameters 
Laboratory test 
Character value 
50% Lower limit of detection 
(LLOD) 
Absolute Monocytes 
ABSMON < 0.1 
ABSMON= 0.05 x 109/L 
Absolute Lymphocytes 
ABSLYM < 0.1 
ABSLYM = 0.05 x 109/L 
Alkaline Phosphatase 
ALKPHS < 3  
ALKPHS = 1.5 U/L 


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Amylase 
AMY < 3 
AMY= 1.5 U/L 
SGOT (AST) 
SGOT < 5 
SGOT = 2.5 U/L 
SGPT (ALT) 
SGPT < 4  
SGPT = 2 U/L 
Gamma Glutamyltransferase (GGT) 
GGT < 5 
GGT = 2.5 U/L 
Bilirubin (total) 
TBIL < 2  
TBIL = 1 µmol/L 
Bilirubin (direct/conjugated) 
DBIL < 3 
DBIL = 1.5 µmol/L 
HCG 
HCG < 2  
HCG = 1 IU/L 
Herpes Simplex Virus 2 IgG 
HSVIGG4 < 0.5 
HSVIGG4= 0.25 
IgG antibody to varicella zoster 
virus 
IGGVZV2 < 10 
IGGVZV2 =5 U/L 
Glucose 
GLUC < 1 mmol/L 
GLUC= 0.5 mmol/L 
Urine Protein Dipstick test 
UPROTST < 0.1 
UPROTST =0.05 
 
Table 4-4 Abnormal criteria 
Laboratory Variable (unit) 
Criteria 
Albumin (g/L) 
<LLN 
Bilirubin (direct/conjugated) 
(umol/L)) 
>ULN 
>2xULN 
Gamma Glutamyltransferase (GGT) 
(U/L) 
>ULN 
>3xULN 
Glucose (mmol/L) 
>ULN 
Cholesterol (HDL) (mmol/L) 
>ULN 
Cholesterol (LDL) (mmol/L) 
>ULN 
SGOT (AST) (U/L) 
>ULN 
>2xULN 
>3xULN 
>5xULN 
SGPT (ALT) (U/L) 
>ULN 


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>2xULN 
>3xULN 
>5xULN 
Cholesterol (total) (mmol/L) 
>ULN 
8.2.3 
Data Summaries for lab tests 
All lab parameters (excluding all hematology % values except % for white cell differential values) will 
be summarized.  
Summaries on the safety set by treatment group include:  
• 
Summary statistics of lab results (hematology, biochemistry, and urinalysis) by visit 
• 
Changes from baseline in lab results (hematology, biochemistry, and urinalysis) by visit 
• 
Summary statistics of percent of baseline in hematology results by visit 
• 
Incidence rates of newly occurring or worsening abnormalities based on clinically notable 
laboratory abnormality criteria (based on criteria in Table 4-2) 
• 
Incidence rates of clinically notable laboratory abnormalities by visit 
• 
Incidence rates of laboratory results meeting abnormal criteria (in Table 4-4) by visit 
• 
Frequency (%) distributions of liver function test results and hematology results in pre-
defined categories (as specified in the table shells) 
• 
Shift table (low, normal, or high as defined by the normal ranges) from baseline to post-
baseline extreme values in hematology,  biochemistry and continuous urinalysis results 
• 
Shift table (negative, +, 2+, 3+, or 4+) from baseline to post-baseline extreme values in 
urinalysis results  
• 
Frequency (%) distributions of serology results for subjects with serology test 
Summaries on the follow-up set by treatment group include: 
• 
Summary statistics of lab parameters (hematology, biochemistry, and urinalysis) by visit 
• 
Change from baseline in lab parameters (hematology, biochemistry, and urinalysis) by visit 


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8.3 
Vital signs 
8.3.1 
Vital signs measurements 
The vital sign CRF collects systolic blood pressure (SBP) and diastolic blood pressures (DBP), pulse, 
body temperature, and body weight. The mean arterial blood pressure will be derived from the DBP 
and SBP using the formula below 
• Mean arterial blood pressure = [2*DBP + SBP]/3. 
Before the protocol amendment 1, the CRF collects vital signs only at sitting position at each visit. 
After the protocol amendment 1, the CRF collects vital signs at supine and standing position at each 
visit  
For all visits (excluding the first or second or restart dose monitoring data) one measurement of pulse 
and 3 measurements of blood pressure (SBP and DBP) are collected before the protocol amendment 
1 and three measurements of pulse and blood pressure (SBP and DBP) are collected.  
At first or second or restart dose monitoring, pulse, SBP and DBP are measured 3 times at the 
scheduled pre-dose time point.  The average of available values among three pulse ( or SBP or DBP) 
measurements at the same position will be calculated. 
For post-baseline assessments (excluding the first or second or restart dose monitoring data), the 
pulse or blood pressure value will be the average of the non-missing values of the 3 measurements, if 
it is not a single measurement, at the same position. If more than one blood pressure assessment 
after the average of the 3 measurements at the same position at the same date (scheduled or 
unscheduled, except for the first dose or second dose or restart dose monitoring data) exists in a 
particular visit as defined by the visit windows, the blood pressure value will be the average of all 
assessments at the same position.  
The vital sign (pulse, SBP and DBP) during the first dose administration on Day 1 or Day 2 and restart 
data will not be put into visit windows, but will be summarized separately by the hour in which the 
measurement was reported. 
8.3.2 
Vital signs notable criteria 
Clinical notable criteria in vital signs are summarized in Table 4-5. 
Table 4-5 Criteria for clinically notable vital signs 
Vital Sign Variable 
Notable Criteria 
Pulse (beats/min) 
>120bpm or Increase of ≥15 bpm from baseline 
or 
< 50bpm or Decrease of ≥15 bpm from baseline 
Systolic BP (mmHg) 
≥160 mm Hg or Increase of ≥20 mm Hg from baseline 
or 


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≤ 90 mm Hg or Decrease of ≥ 20 mm Hg from baseline 
Diastolic BP (mmHg) 
≥ 100 mmHg or Increase of ≥ 15 mm Hg from baseline 
or 
≤ 50 mmHg or Decrease of ≥ 15 mm Hg from baseline 
Temperature (°C) 
>38.3 °C/101°F 
Body weight (kg) 
± ≥ 7% from baseline weight 
8.3.3 
Data summaries for vital signs 
Pulse and blood pressure will be reported separately for sitting, supine and standing position. 
Incidence rates of clinically notable, post-baseline abnormalities and orthostatic hypotension will be 
provided by treatment. Orthostatic hypotension is defined as a reduction of systolic blood pressure 
of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg from supine to standing 
position. 
The following summaries will exclude hourly vital sign data from the first dose or second dose or 
restart dose monitoring. 
Summaries on the safety set by treatment group include:  
• 
Summary statistics of vital sign parameters by visit 
• 
Changes from baseline in vital sign parameters by visit 
• 
Frequency (%) distributions of highest SBP, DBP, and lowest pulse in pre-defined categories 
respectively 
• 
Incidence rates of notable vital sign abnormalities based on the notable criteria in Table 4-5 
• 
Incidence rates of orthostatic hypotension by treatment and visit 
Summaries on the follow-up set by treatment group include: 
• 
Summary statistics of vital sign parameters by visit 
• 
Change from baseline of vital sign parameters by visit                                                                                                      
8.4 
Electrocardiograms (ECG) 
The ECG data includes quantitative variables such as ventricular rate, PQ or PR interval, R-R interval, 
QRS duration, and uncorrected QT interval as well as categorical variables such as ECG interpretation 
(normal or abnormal), ECG evaluation type (rhythm, conduction, etc) and ECG findings (prolonged 
QTc, low voltage, etc).  


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8.4.1 
Corrected QT interval 
The uncorrected QT interval will be corrected using the Bazett and Fridericia formulas. The Bazett 
formula corrects the QT interval by dividing by the square root of the R-R interval (secs). The 
Fridericia formula corrects the QT interval by dividing by the cubic root of the R-R interval (secs). 
8.4.2 
Abnormality criteria for corrected QT interval 
Abnormality criteria for the corrected QT interval (Bazett and Fridericia) are listed in Table 4-6. 
Table 4-6 Abnormality criteria for corrected QT interval 
 
 Male Subjects 
Female Subjects 
1 
>450 msec 
>470 msec 
2 
>500 msec 
>520 msec 
3 
30 - 60 msec increase from Baseline 
4 
>60 msec increase from Baseline 
 
8.4.3 
ECG findings 
ECG findings are associated with the ECG evaluation type and thus will be summarized by the ECG 
evaluation type.  
8.4.4 
Data summaries for ECG data 
The following summaries will exclude ECG data from the first dose or second dose or restart dose 
monitoring.  
Summaries on the safety set by treatment group include:  
• 
Summary statistics of quantitative ECG parameters by visit 
• 
Changes from baseline in quantitative ECG parameters by visit 
• 
Incidence rates of abnormal corrected QT interval (Bazett and Fridericia) as defined by the 
abnormality criteria in Table 4-6 
• 
Frequency (%) distribution of ECGs interpretation (normal/abnormal) by visit 
• 
Frequency (%) distribution of ECG findings by ECG evaluation type by visit 
 
Note: For this study the only post-baseline visit is Month 12/EOT (end of treatment). So, all 
summaries above will be present for Baseline and then Month 12/EOT. 


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8.5 
Pulmonary function tests (PFT) 
8.5.1 
Predicted values and units of PFTs 
For each subject, the predicted values of the PFT parameters (Forced expiratory volume in 1 second 
(FEV1), Forced vital capacity (FVC), FEV1/FVC, and Diffusion capacity of carbon monoxide (DLCO)) will 
be calculated based on the formulas below. 
Reference equations to calculate the predicted values of FEV1, FVC, FEV1/FVC 
• 
Forced expiratory volume in one second (FEV1) (Unit: Liter/second):  
male: (4.3 · height (m)) – (0.029 · age (yr)) – 2.49 [±0.51]  
female: (3.95 · height (m)) -  (0.025 · age (yr)) – 2.6 [±0.38] 
• 
Forced vital capacity (FVC) (Unit: Liter):  
male: (5.76 · height (m)) – (0.026 · age (yr)) – 4.34 [±0.61]  
female: (4.43 · height (m)) – (0.026 · age (yr)) – 2.89 [± 0.43]  
• 
FEV1/FVC (Unit: %): 
male:  - 0.18 · age (yr) + 87.21 [± 7.17]   
female: 0.19 · age (yr) + 89.10 [± 6.51]   
Reference equations to obtain predicted values of DLCO 
• 
Single breath diffusion capacity (DLCO) (Unit: ml/min/mmHg): 
Male: (0.3319 · height (cm)) – (0.1971 · age (yr)) – 18.006  
Female: (0.2441 · height (cm)) – (0.1436 · age (yr)) – 8.20 
In the above calculations, the height of a subject is from the screening visit and the age should be 
calculated based on the date when he or she performs the PFTs.  
For DLCO, three units may be collected in the CRFs, which are ml/min/torr, ml/min/mmHg, and 
mmol/min/kpa. The PFT tables and listings will use the unit ml/min/mmHg. The other two units will 
be converted to ml/min/mmHg, prior to any calculations, as follows: 
• 
1 ml/min/torr = 1 ml/min/mmHg; 
• 
1 mmol/min/kpa = 2.986 ml/min/mmHg. 
8.5.2 
Percent predicted PFTs 
The percent predicted PFT value, for each subject, is defined as (absolute PFT value / predicted PFT 
value) * 100. 
The change from baseline in percent predicted PFT value is defined as (post-baseline percent 
predicted PFT value - baseline percent predicted PFT value).  
The percent of baseline in absolute value of a PFT is calculated as (post-baseline absolute PFT value / 
baseline absolute PFT value) * 100. 


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The percent predicted PFT value will be categorized by pre-defined intervals. Details will be specified 
in the table shell document (RAP Module 7.1) 
Relevant PFT changes are defined as below 80% of baseline and below 60% of baseline in absolute 
PFT values at 2 consecutive visits. 
For non by-visit summaries, visits defined by visit windows will not be used. All available data from 
scheduled and unscheduled visits will be considered when checking 2 consecutive visits.  
8.5.3 
Data summaries for PFTs 
Summaries on the safety set by treatment group include: 
• 
Summary statistics in absolute values of FEV1, FVC, FEV1/FVC, and DLCO and in percent 
predicted values of FEV1, FVC, FEV1/FVC, and DLCO by visit 
• 
Changes from baseline in absolute values of FEV1, FVC, FEV1/FVC, and DLCO and in percent 
predicted values of FEV1, FVC, FEV1/FVC, and DLCO by visit 
• 
Number (%) of subjects meeting the following criteria as compared to the baseline 
(separately for FEV1, FVC, DLCO): below 80% at any visit; below 80% at 2 consecutive visits; 
below 60% at any visit; and below 60% at 2 consecutive visits 
• 
Shift tables from baseline to the lowest post-baseline values in pre-defined categories of the 
percent predicted values of FEV1, FVC, and DLCO 
• 
Number (%) of subjects with relevant PFT changes (for FEV1, FVC, and DLCO) by baseline 
percent predicted PFT categories 
Summaries on the follow-up set include: 
• 
Summary statistics in absolute values of FEV1, FVC, FEV1/FVC, and DLCO and in percent 
predicted values of FEV1, FVC, FEV1/FVC, and DLCO by visit 
• 
Change from baseline in absolute values of FEV1, FVC, FEV1/FVC, and DLCO and in percent 
predicted values of FEV1, FVC, FEV1/FVC, and DLCO by visit 
 
Note: Site 
 had 5 subjects with unrealistic values (>80L) reported for FEV1/FVC in the CRF. The 
site is not responsive. On August 22nd, 2018, the study team reviewed the issue and agreed to set 
them as missing (unknown) in the analysis.  
8.6 
Ophthalmic evaluations 
The ophthalmic evaluation includes assessment of visual acuity, assessment of optical coherence 
tomography (OCT), fluorescein angiography, and assessment of macular edema. 


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For the assessment of visual acuity, if the decimal score is not available but the Corrected Snellen 
equivalent is available, the decimal score will be calculated by division (e.g., Corrected Snellen 
equivalent = 10/20 infers that decimal score = 0.5). All decimal scores will be converted to the 
LogMAR (log of the minimum angle of resolution) equivalent by taking the negative of the common 
logarithm (i.e., -log10 (decimal acuity score)) (Holladay 1997). Summaries of the visual acuity will be 
performed on the converted scores (i.e., LogMAR equivalent). 
If two or more visual acuity values for the same eye of a subject are available at a post-baseline visit 
window, the worst of all values will be used in the summaries. Note that the worst value for visual 
acuity refers to the smallest value in the decimal score (or equivalently refers to the largest value in 
the logMAR scale). 
Visual acuity and change from baseline in visual acuity will be categorized by pre-defined intervals. 
Details will be specified in the table shell document (RAP Module 7.1). 
The central foveal thickness (CFT), macular volume data from OCT and fluorescein angiography data 
will be displayed in listings. 
8.6.1 
Data summaries for ophthalmic evaluations 
Summaries on the safety set by treatment group include: 
• 
Summary statistics of visual acuity by visit 
• 
Changes from baseline in visual acuity by visit 
• 
Frequency (%) distribution of categorized visual acuity by visit 
• 
Frequency (%) distribution of categorized change from baseline in visual acuity by visit 
• 
Summary of diagnosis of macular edema 
8.7 
Dermatology assessment 
Dermatology examinations will be performed at screening, and Month 12/end of study visits 
according to a protocol. Results of the dermatology exams are categorical (normal or abnormal with 
abnormal types) and will be summarized by treatment group for each visit as well as for the 
unscheduled visit.  For unscheduled visit summary, if a subject has 2 or more unscheduled 
assessments, only the worst result will be summarized. 
One shift table from baseline assessment to Month 12/end of treatment assessment will also be 
presented. 


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8.8 
First dose (second dose or restart dose) of fingolimod 
monitoring 
8.8.1 
Vital signs 
Hourly vital signs including pulse, SBP and DBP are collected at pre-dose and 6 hours after the first 
dose, second dose (if necessary), and restarting of dose after interruption (if applicable). The resting 
pulse and its change from pre-dose and percent change from pre-dose will also be categorized by 
pre-specified cutoffs as given in the table shells. The bradycardia events, bradycardia symptoms, and 
bradycardia treatment during the first dose, second dose (if necessary), and restarting of dose after 
interruption (if applicable) monitoring will be collected and summarized as well.  
The bradycardia events, bradycardia symptoms, and bradycardia treatment will be collected on the 
corresponding CRFs. Note: Bradycardia events that do not have symptoms or require treatment are 
not collected in those CRFs and they are recorded in the Adverse Event CRF.  
8.8.2 
ECG 
ECG will be performed at pre-dose and 6 hours post dose during the first dose, second dose (if 
necessary), and restarting of dose after interruption (if applicable) monitoring. 
8.8.3 
Dose monitoring experience 
The overall dose monitoring experience refers to the following information: whether subjects are 
discharged after 6 hours post-dose or extended monitoring is required after 6 hours post-dose, 
whether subjects are hospitalized, whether subjects are required monitoring on the next day, 
whether subjects have symptomatic and/or treated bradycardia, whether subjects discontinue the 
study drug permanently, whether SAE is reported, and whether subjects are discharged but returned 
to clinic. 
8.8.4 
Data summaries for first dose monitoring 
Summaries on the safety set by treatment group include: 
• 
Summary statistics of vital signs by hour (1st dose, 2nd dose, and restarts) 
• 
Changes from pre-dose in vital signs by hour (1st dose, 2nd dose, and restarts) 
• 
Frequency (%) distribution of categorized supine and standing pulse or change (or percent 
change) from pre-dose supine and standing pulse during first dose administration, 
respectively 
• 
Summary of the overall dose monitoring experience (1st dose, 2nd dose, and restarts) 
• 
Incidence rates of bradycardia events (1st dose and 2nd dose) 
• 
Incidence rates of medications used for bradycardia (1st dose and 2nd dose) 


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• 
Incidence rates of bradycardia symptoms by SOC, PT, and severity (1st and 2nd dose) 
• 
Incidence rates of notable vital sign abnormalities based on the notable criteria in Table 4-5 
(1st dose and 2nd dose) 
• 
Summary statistics of ECG parameters by time point during 1st and 2nd dose administration  
• 
Changes from pre-dose in ECG parameters by time point during 1st and 2nd dose 
administration 
• 
Incidence rates of abnormal QTc interval (Bazett and Fridericia) as defined by the 
abnormality criteria in Table 4-6 during 1st and 2nd dose administration 
• 
Frequency (%) distribution of ECGs interpretation (normal/abnormal) by time point during 1st 
and 2nd dose administration 
• 
Frequency (%) distribution of ECG findings by ECG evaluation type by time point during 1st 
and 2nd dose administration 
8.9 
Columbia Suicide Severity Rating Scale (C-SSRS) 
General 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively assesses 
suicidal ideation and behavior (SIB). There are two versions of the questionnaire: 
• 
The “baseline/screening” version, which is to be performed at the first visit (Visit 1). It 
assesses SIB during the subject’s lifetime.  
• 
The “since last visit” version to be used at subsequent visits (Visit 2 to Visit 7), assessing SIB 
since last visit. 
A copy of the questionnaires can be found in protocol amendment Appendix or CRF package. 
The 11 categories described in Table 7-1 have been adopted as standard by FDA to report SIB ([Food 
and Drug Administration, 2012], [Nilsson et al, 2013]). These categories include five levels of suicidal 
ideation, five levels of suicidal behavior and the category self-injurious behavior, no suicidal intent. 
Each category has a binary response (yes/no). The C-SSRS questionnaire allows suicidal ideation and 
behavior to be classified into these 11 preferred categories. 
Note: the categories in Table 7-1 have been reordered (based on [Nilsson et al 2013]) compared to 
the categories in the actual C-SSRS (paper) scale and the categories listed in the FDA guidance, in 
order to facilitate the definitions of endpoints and enable clarity in the presentation of results. 
Table 7-1 
Standard SIB events  
Category 
number 
C-SSRS category 
Suicidal Ideation 


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Category 
number 
C-SSRS category 
1 
   Wish to be dead 
2 
   Non-specific active suicidal thoughts 
3 
   Active suicidal ideation with any methods (not plan) without intent to act 
4 
   Active suicidal ideation with some intent to act, without specific plan 
5 
   Active suicidal ideation with specific plan and intent 
Suicidal behavior 
6 
   Preparatory acts or behavior 
7 
   Aborted attempt 
8 
   Interrupted attempt 
9 
   Actual attempt 
10 
   Completed suicide 
Self-injurious behavior, without suicidal intent 
11 
   Non-suicidal self-injurious behavior 
 
In this study, the C-SSRS questionnaire will be administered electronically (eC-SSRS), via an 
interactive voice response (IVR) system with the patient entering responses directly into the IVRS. 
Caregivers will not be allowed to answer the C-SSRS questions on behalf of the patient. Sites must 
review reports received from the system for any answers indicative of suicidal ideation and adverse 
event AEs. Adverse events ascertained through the administration of the C-SSRS will be documented. 
No safety cut-off will be applied for the SIB data reporting, i.e. all collected data will be used in the 
analysis including data collected off-treatment, if any. 
Definition of ‘all prior history’  
All prior history will be defined as the SIB results obtained from the lifetime assessment at the first 
visit (Visit 1).  
Worst case is defined by an answer ‘yes’ to the SIB category.  
Data summaries at the study level 
SIB data will be summarized for the Safety Set. The number and percentage of subjects with suicidal 
ideation, suicidal behavior and self-injurious behavior without suicidal intent will be presented by 
analysis-period (all prior history and any time post-baseline) and treatment group. The following 14 
events will be included in the summary table: 
• 
Each of the 11 categories listed in Table 7-1, separately  
• 
Any suicidal ideation or behavior (a ‘yes’ answer  to at least one of the 10 suicidal ideation 
and behavior questions in analysis-period of interest) 
• 
Any suicidal ideation (answered ‘yes’ to at least one of the 5 suicidal ideation questions in 
analysis-period of interest) 


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• 
Any suicidal behavior (answered ‘yes’ to at least one of the 5 suicidal behavior questions in 
analysis-period of interest). 
For those analyses, each subject can only be counted once for each event. However, a subject can be 
counted in several different events. 
Suicidal ideation and behavior data will be listed. Detailed answers to C-SSRS items will be listed 
separately for subjects with any suicidal ideation at any time post-baseline (i.e. a ‘yes’ answer to at 
least one of the five suicidal ideation questions at any time post-baseline) and for subjects with any 
suicidal behavior at any time post-baseline (i.e. a ‘yes’ answer to at least one of the five suicidal 
behavior questions at any time post-baseline). 
 
9 
Interim analyses 
No efficacy interim analyses are planned. On an as-needed basis, safety interim analysis for the 
DSMB will be performed by an independent statistician and independent statistical programmer. The 
analysis plan for these safety interim analyses will be provided in a separate document. 
10 
Determination of sample size 
The study will randomize a total of 1960 patients, and is planned to provide approximately 90% 
power for the comparison of fingolimod 0.5 mg to glatiramer acetate at a 2-sided significance level of 
0.05.   
The sample size calculation is based on simulations from a negative binomial distribution with a 
constant dispersion parameter k.  
The power of the study was evaluated under various ARR assumptions and various dropout patterns 
based on the cumulative literature on glatiramer acetate and the Novartis data on fingolimod. The 
basis of the assumptions for this study and their level of uncertainty are presented in Section 9.4.2 
under the sub-header “Multiplicity adjustment for statistical hypothesis testing”. The anticipated 
overdispersion parameter (k=0.2231) was observed in the Month-12 analysis of Study 
CFTY720D2301. The anticipated ARR for subjects treated with 0.5 mg fingolimod is µFTY 0.5 mg = 0.195, 
the ARR for those  treated with glatiramer acetate is µglatiramer acetate = 0.30. Therefore, the estimated 
ARR reduction for fingolimod 0.5 mg versus glatiramer acetate is 35%.  
The total sample size of 1960 randomized is predetermined but the exact sample size of each arm 
will depend on when the randomization ratio switch occurs. For example, if the randomization ratio 
is switched when a total of 800 patients have been randomized from an original ratio of 1:1:1 for 
fingolimod 0.25 mg, fingolimod 0.5 mg, or glatiramer acetate, respectively to a ratio of 5:3:2, then 
847 patients will be randomized to fingolimod 0.25 mg, 615 patients to fingolimod 0.5 mg and 498 
patients glatiramer acetate, which will provide more than 90% power to demonstrate superiority of 
fingolimod 0.5 mg dose versus glatiramer acetate in terms of ARR at a 2-sided significance level of 


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0.05 assuming a 15% drop-out rate. The calculations take into account that patients who discontinue 
prematurely from the study can participate with partial data to the primary endpoint. 
Fingolimod 0.25 mg has never been studied in a clinical trial in MS. Based on PK/PD modeling results, 
it is anticipated that the ARR in subjects treated with fingolimod 0.25 mg is approximately 15% higher 
than in those treated with fingolimod 0.5 mg. However, the uncertainty of this estimate is high; the 
95% confidence interval of the estimated ARR in fingolimod 0.25 mg group ranges from 0.18 to 0.30. 
It is therefore anticipated that fingolimod 0.25 mg is less efficacious than fingolimod 0.5 mg, but 
more efficacious than glatiramer acetate. In line with the PK/PD modeling the anticipated ARR in 
subjects treated with fingolimod 0.25 mg is µFTY 0.25 mg = 0.225, which corresponds to a reduction in 
ARR of 25% in subjects treated with fingolimod 0.25 mg compared to those treated with glatiramer 
acetate.  
Following the multiplicity adjustment procedure in Multiplicity adjustment section 4.2.1.1, the power 
to detect a 25% reduction in ARR for subjects treated with fingolimod 0.25 mg compared with 
subjects treated with glatiramer acetate is approximately 68% at a 2-sided significance level of 0.05, 
if the primary objective for the fingolimod 0.5 mg dose can be rejected first; the corresponding 
marginal power with multiplicity adjustment is approximately 61%. If fingolimod 0.25 mg is similarly 
efficacious as fingolimod 0.5 mg (i.e., ARR reduction versus glatiramer acetate is 35% rather than 
25%), the power to detect this treatment effect at a 2-sided significance level of 0.05 is 
approximately 88%. If fingolimod 0.25 mg is similarly efficacious as glatiramer acetate (i.e., estimated 
ARR in the fingolimod 0.25 mg group is at the high end of range proposed by the PK/PD model), there 
will be no significant difference at a 2-sided significance level of 0.05. 
Due to the study early termination approved in December 2016 the final number of randomized 
patients is 1064 with 370 for fingolimod 0.25 mg, 352 for fingolimod 0.5 mg and 342 for glatiramer 
acetate. The statistical power based on the final sample size is approximately 71% for comparison of 
fingolimod 0.5 mg vs glactiramer acetate. For the comparison of fingolimod 0.25 vs glactiramer 
acetate the statistical power is approximately 44% without multiplicity adjustment and 31% with 
multiplicity adjustment. 
The statistical software R (Version 2.13.1, open source) and the R library packages “MASS” and 
“PSCL” were used for sample size calculations and power analysis. 
11 
Documentation of changes from the protocol 


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12 
Clinical Study Report -  
Appendix 16.1.9 Documentation of statistical methods 
12.1 
Statistical methods and analysis outputs  
12.1.1 
Statistical methods 
Statistical Analysis System (SAS) version 9.2 or higher will be used to perform all the statistical 
analyses in the report. 
Pair-wise treatment comparisons will be performed using separated data for treatment groups (A vs. 
C, B vs. C, and A vs. B) for the following analyses: rank ANCOVA/ANOVA, survival analyses, Wilcoxon 
rank-sum test, and Fisher’s exact test. Data from all treatment groups (A, B, and C) will be used for 
the following analyses: negative binomial regression, logistic regression, and ANCOVA. 
12.1.1.1 Negative binomial regression model  
The primary efficacy variable (aggregate ARR) will be analyzed using a negative binomial regression 
model. This analysis will be performed on the full analysis set and the per-protocol set. All 3 
treatment groups will be used to fit the regression model in the analysis. In addition, the negative 
binomial regression model will be used for several supportive analyses for aggregate ARR and 
number of new or newly enlarged T2 lesions. 


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Negative binomial regression is used for modeling count variables, usually for overdispersed count 
outcome variables, while adjusting for one or more covariates. In general, Negative binomial 
regression analyzes the distributed data in the following form 
~
( ,
),
1,
, .
i
i
i
Y
NB r p
for
i
n
= 
 
where the negative binomial distribution is a discrete probability distribution of the number of 
successes in a sequence of Bernoulli trials before a specified (non-random) number of failures 
(denoted r) occur with a probability p. 
The log of the count variables are modeled as a linear function of the Xi. 
0
1 1,
,
log(
)
i
i
k
k i
y
x
x
β
β
β
=
+
+
+

 
Below is an example of the SAS codes used to perform the analysis of the negative binomial 
regression. The independent variables and covariates in the model may change per analysis defined 
in this document. 
************************************************************************** 
* SAS Codes: Negative binomial regression model  
* Variables in the model:   
* relnum = number of relapses 
* trt = treatment group code 
* reg1a = region code 
* n2 = number of relapses in previous year 
* bledss = baseline EDSS 
* sid1a = subject ID 
* lnday = log(days in study/365.25) 
**************************************************************************; 
proc genmod data=data1; 
     class trt reg1a; 
     model relnum=trt reg1a n2 bledss / dist=nb 
                                        link=log 
                                        offset=lnday maxiter=500 lognb; 
     lsmeans trt /cl; 
     estimate ‘A – B’ trt  1  -1  0/exp;  
     estimate ‘A – C’ trt  1   0 -1/exp;  


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     estimate ‘B – C’ trt  0   1 -1/exp;  
 
     ods output estimates=est; 
     ods output lsmeans=lst; 
run; 
12.1.1.2 Rank Analysis of Covariance (ANCOVA) and Rank Analysis of Variance 
(ANOVA) 
Rank Analysis of Covariance (ANCOVA)  
The supportive efficacy variable, subject-level ARR (confirmed relapse only), will be analyzed using 
the rank ANCOVA. Other secondary efficacy variables, subject-level ARR (confirmed and 
unconfirmed relapse), change from baseline in 
 MRI 
variables, will be analyzed similarly on the full analysis set. 
The rank ANCOVA is a non-parametric statistical method described in Stokes, Davis, and Koch (2000). 
It can be considered as an extension to the Wilcoxon rank-sum test with the ability to adjust for 
covariates in the model.  
The analysis can be easily implemented using SAS by the following three steps:  
1) compute the ranks of the response variable and covariate in the combined group of treatment 
using PROC RANK;  
2) calculate the residuals from the linear regression of the response variable ranks vs.  ranks of the 
covariates (without treatment) using PROC REG;  
3) use the CMH mean score statistics to compare the mean values of the residuals in treatment by 
using TABLE scores (default scores) in PROC FREQ.  
Below is an example of the SAS codes used to perform this rank ANCOVA. The independent variables 
and covariates in the model may change per analysis defined in this document. 
************************************************************************** 
* SAS Codes: Rank ANCOVA model  
* Variables in the model:   
* relann = subject-level annualized relapse rates  
* trt = treatment group code 
* reg1a = region code 
* n2 = number of relapses in previous year 
* bledss = baseline EDSS 


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* other covariates as well 
* sid1a = subject ID 
**************************************************************************; 
Data eff; 
     Set eff; 
     If reg1a=’ ‘ or n2=. or bledss=. or relann=.then delete; 
run; 
 
proc rank data=eff nplus1 ties=mean out=ranks; 
     by reg1a; 
     var n2 bledss relann more convariates…; 
run; 
 
proc reg data=ranks noprint; 
     by reg1a; 
     model relann=n2 bledss more convariates…; 
     output out=residual r=resid; 
run; 
 
proc freq data=residual; 
     tables reg1a*trt*resid / noprint cmh2; 
 
  where trt in (‘A’,’B’); 
     output out=rancova cmh2;     
     *** SELECT P_CMHRMS; 
run; 
 
Rank Analysis of Variance (ANOVA)  
Number of new or newly-enlarged T2 lesions will be analyzed using the rank ANOVA adjusted for 
treatment and region on the full analysis set. Unlike Rank ANCOVA where continuous covariates 
exist, the PROC RANK and PROC REG steps are not necessary. The van Elteren’s test will be used for 
treatment comparisons. The van Elteren’s test is a rank based test and can be implemented in PROC 


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FREQ with options CMH2 and score equal to MODRIDIT. The van Elteren’s test statistic corresponds 
to the row mean scores statistic labeled “Row Mean Scores Differ” in the CMH output.  
Below is an example of the SAS codes used to perform this rank ANOVA. The independent variables 
and covariates in the model may change per analysis defined in this document. 
************************************************************************** 
* SAS Codes: Rank ANOVA model  
* Variables in the model:   
* RSLVAL1N = number of new or newly-enlarged T2  
* trt = treatment group code 
* reg1a = region code 
* sid1a = subject ID 
**************************************************************************; 
proc freq data= eff; 
     where trt in (‘A’,’B’); 
     tables reg1a*trt*RSLVAL1N / noprint cmh2 scores=MODRIDIT; 
     output out=ranova cmh2;     
     *** SELECT P_CMHRMS; 
run; 
 
12.1.1.3 Logistic regression for proportion variables  
The other secondary/other efficacy variables (
, proportion of 
subjects free of new or newly enlarging T2 lesions, proportion of subjects free of Gd + lesions, 
proportion of subjects free of new T1 lesion) will be analyzed using the logistic regression on the full 
analysis set. All 3 treatment groups will be used in the model. 
Logistic regression is a model for prediction of the probability of occurrence of an event. It can be 
used to analyze the dichotomous response data while adjusting for one or more covariates. Usually, 
Logistic regression analyzes binomially distributed data of form 
.
,
,1
),
,
(
~
n
i
for
p
n
B
Y
i
i
i

=
 
The logits of the unknown binomial probabilities (i.e., the logarithms of the odds) are modeled as a 
linear function of the Xi. 
.
)
1
log(
,
,1
1
0
i
k
k
i
i
i
x
x
p
p
β
β
β
+
+
+
=
−

 


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Below is an example of the SAS codes used to perform the analysis of the LOGISTIC regression. The 
independent variables and covariates in the model may change per analysis defined in this 
document. 
************************************************************************** 
* SAS Codes: LOGISTIC model  
* Variables in the model:   
* mrifree = proportion of subjects free of Gd + lesions  
* reg1a = region code 
* blmri = baseline number of Gd + lesions 
* more covariates could be added as needed 
**************************************************************************; 
proc logistic data=eff descending; 
     class reg1a trt /param=ref; 
     model mrifree = reg1a trt blmri (more covariated as needed); 
 
     contrast ' A – B '  trt  1 -1  0/estimate=exp; 
     contrast ' A – C '  trt  1  0 -1/estimate=exp; 
     contrast ' B – C '  trt  0  1 -1/estimate=exp; 
 
 
  ods output Contrastestimate=est; 
run; 
 
 
For this study, proc logistic is performed including all 3 treatment levels with the contrast specifying 2 
levels. 
12.1.1.4 Survival analysis for time to event variables 
Log-rank test will be used to compare the survival distributions of two treatment groups for 
secondary efficacy time to event variables, 
. These 
analyses will be performed on the full analysis set. 
The logrank test is a hypothesis test to compare the survival distributions of two samples. It is a 
nonparametric test and appropriate to use when the data are right skewed and censored 
(technically, the censoring must be non-informative). It is constructed by computing the observed 


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and expected number of events in one of the groups at each observed event time and then adding 
these to obtain an overall summary across all time points where there is an event.  
Cox proportional hazards model is to estimate the effect parameter(s) without any consideration of 
the hazard function assuming the proportional hazards assumption holds. The proportional hazards 
assumption is the assumption that effect parameters multiply hazard: for example, if taking drug X 
halves your hazard at time 0, it also halves your hazard at time 1, or time 0.5, or time t for any value 
of t. The effect parameter(s) estimated by any proportional hazards model can be reported as hazard 
ratios.  
Below is an example of the SAS codes used to perform the Log-rank test with Kaplan-Meier Method 
and the Cox proportional hazards model. The independent variables and covariates in the model may 
change per analysis defined in this document. 
************************************************************************** 
* SAS Codes: LOG-RANK test with Kaplan-Meier Method   
* Variables in the model:   
* reltm = 
 
* trt = treatment group code 
* relcens = censor flag (1=censored, 0=not censored)  
**************************************************************************; 
proc lifetest data=eff method=km; 
     where trt in (‘A’,’B’); 
     time reltm*relcens(1); 
     strata trt; 
run; 
************************************************************************** 
* SAS Codes: Cox’s regression model   
* Variables in the model:    
* reltm = 
 
* trt = treatment group code 
* reg1a = region code 
* n2 = number of relapses in previous year 
* bledss = baseline EDSS 
* relcens = censor flag (1=censored, 0=not censored) 
* more covariates could be added as needed 


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**************************************************************************; 
***include all 3 treatment arms data in one model fitting*** 
proc phreg data=datain nosummary; 
  class trt reg1a 
  model reltm*relcens(1)=trt n2 bledss reg1a (more covariates as needed)/rl 
ties=exact; 
  contrast “A vs C” trt 1 0 -1/estimate=exp; 
  contrast “B vs C” trt 0 1 -1/estimate=exp; 
  contrast “A vs B” trt 1 -1 0/estimate=exp; 
  ods output parameterestimates=pest; 
  ods output contrastestimate=est; 
run; 
**Note that data set pest contains Hazard ratio estimates from model 
statement where only A vs C and B vs C are available. If parameter=’trt’, 
then SELECT probchisq hazardratio hrlowercl hruppercl for results; 
**However, data set est contains Hazard ratio estimates from contrast 
statement where all 3 pairwise comparisons are available (result variable 
names: estimate lowerlimit upperlimit probchisq); 
12.1.1.4.1 Estimation of 95% confidence intervals 
Approximate 95% confidence intervals will be generated for several estimates: (1) at selected time-
points, the (Kaplan and Meier 1958) estimates of the proportion of subjects experiencing a specific 
event, (2) at selected time-points, the between-treatment group difference in Kaplan-Meier 
estimates of the proportion of subjects experiencing a specific event, (3) for certain study periods, 
the between-treatment group difference in the proportion of subjects experiencing a specific event, 
and (4) at selected time-points, the between-treatment group difference in means. Details of such 
confidence intervals are displayed in Table 5-1. 
Table 12-1 Confidence Interval calculations 
 
Approximate Confidence Interval (CI) 
Lower Limit 
Upper Limit 
1 x% CI for the Kaplan-Meier estimate KM 
KM - cx*SE 
KM + cx*SE 
Notation: SE  =  estimated standard error of KM; 
                            estimation of standard error uses Greenwood’s formula, 
                 cx    = Φ-1(½ + x/200), where Φ is the normal distribution function. 
2 x% CI for the difference in Kaplan-Meier 
estimates KM2-KM1 
KM2-KM1 - cx*SEd 
KM2-KM1 + cx*SEd 


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Notation: KMi  = Kaplan-Meier estimate for group i = 1,2, 
                 SEd  = √(SE12  + SE22), where SEi2 = estimated standard error of KMi, i = 1,2; 
                            estimation of standard error uses Greenwood’s formula, 
                 cx     = Φ-1(½ + x/200), where Φ is the normal distribution function. 
Examples: for x = 95, cx = Φ-1(0.975) = 1.95996; for x = 97.5, cx = Φ-1(0.9875) = 2.24140 
12.1.1.5 Between-treatment group comparisons for other efficacy variables  
Generally, non-stratified, non-parametrical tests will be used to perform between-treatment group 
comparisons on MS confirmed relapse characteristics and change from baseline in disability, MRI 
variables (Gd + T1 lesion count, T2 lesion volume, Gd + lesion volume, T1 hypointense lesion volume, 
and changes from baseline in  T2 lesion volume and Gd + lesion volume, percentage change from 
baseline in brain volume). Tests applied will be the rank ANCOVA. For a small number of 
comparisons, Wilcoxon rank-sum test for continuous variables will be utilized; Fisher’s exact test will 
be used for categorical variables; for variables with more than five categories it will be replaced with 
the chi-square test. Wilcoxon rank-sum test is also used for comparison between the treatment 
groups 
.  
Below is an example of the SAS codes used to perform these analyses. 
************************************************************************** 
* SAS Codes: Wilcoxon rank-sum test  
* Variables in the model:   
* 
 
* trt = treatment group code 
**************************************************************************; 
proc npar1way data=eff wilcoxon noprint; 
     where trt in (‘A’,’B’); 
     class trt; 
     var C_MSACT;  
run; 
************************************************************************** 
* SAS Codes: Fisher’s exact test  
* Variables in the model:   
* pevt = 1-subject with confirmed relapses;  
         0-subject without confirmed relapses; 


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* trt = treatment group code 
**************************************************************************; 
proc freq data=eff noprint; 
     where trt in (‘A’,’B’); 
     tables trt*pevt / exact; 
run; 
* Select p-value for normal approximation from Wilcoxon Two-Sample Test 
12.1.1.6 Analysis of Covariance (ANCOVA) for quality of life (QoL) variables 
The quality of life variables:
 
 
 
 
************************************************************************** 
* SAS Codes: ANCOVA model  
* Variables in the model:   
* c_msphs = 
 
* trt = treatment group code 
* reg1a = region code 
* age_1n = age at baseline 
* 
 = 
 
**************************************************************************; 
proc mixed data=input dataset; 
     class reg1a trt; 
     
 
     lsmeans  trt /pdiff cl; 
run; 
 
One sample t-test for quality of life (QoL) variables 
The regular one-sample t-test will be used to perform within-group comparisons of continuous (or 
quantitative) efficacy variables where the normality assumption is held reasonably well. The within-


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group analyses for continuous / quantitative variables will compare assessments for the end of 
treatment vs. baseline within each treatment group. Examples of such analysis include the within 
group comparisons of the quality of life variable: change from baseline in TSQM total score.  
Below is an example of the SAS codes used to perform the analysis. All 3 treatment groups will be 
used in the model. 
************************************************************************** 
* * SAS Codes: One sample t-test 
* V1 = First timepoint --- e.g.:(baseline); 
* V2 = Second timepoint --- e.g.:(post-baseline visit, end of treatment); 
* PID = Subject ID or number of observations; 
* diff= difference between two timepoints (higher scores indicate better 
results); 
* NOTE: First, prepare and extract the data for each treatment group. 
* Then, in each treatment group, break up the data into the 2 timepoints. 
* Ensure that each subject has a value at both timepoints (V1 and V2).  
**************************************************************************; 
data one; 
   input PID V1 V2; 
   diff = V2 – V1; 
    
proc ttest data = one sides=u; 
   by treat; 
   var = diff; 
run; 
 
12.1.1.7 Wilcoxon sign test for quality of life (QoL) variables 
Wilcoxon signed-rank test (also known simply as the Wilcoxon sign test) can be thought of as the 
non-parametric equivalent of the regular one-sample t-test. It will be used to perform all within-
group comparisons of continuous (or quantitative) efficacy variables. The within-group analyses for 
continuous / quantitative variables will compare assessments for the end of treatment vs. baseline 
within each treatment group. Examples of such analysis include the within group comparisons of the 
quality of life variable: change from baseline in TSQM total score.  


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Below is an example of the SAS codes used to perform the analysis. All 3 treatment groups will be 
used in the model. 
************************************************************************** 
* * SAS Codes: Wilcoxon signed-rank test (or Wilcoxon sign test) 
* V1 = First timepoint --- e.g.:(baseline); 
* V2 = Second timepoint --- e.g.:(post-baseline visit, end of treatment); 
* PID = Subject ID or number of observations; 
* diff= difference between two timepoints; 
* NOTE: First, prepare and extract the data for each treatment group. 
* Then, in each treatment group, break up the data into the 2 timepoints. 
* Ensure that each subject has a value at both timepoints (V1 and V2).  
**************************************************************************; 
data one; 
   input PID V1 V2; 
   diff = V2 – V1; 
    
proc univariate data = one; 
   by treat; 
   var = diff; 
run; 
12.1.2 
Statistical analysis outputs 
Results from the primary and secondary efficacy analyses will be presented in Section 16.1.9 of the 
clinical study report. 
The list of outputs that will be generated is provided in RAP Module 7.1. 
13 
References 
Atkinson MJ, Sinha A, Hass SL et al.  Validation of a general measure of treatment satisfaction, the 
Treatment Satisfaction Questionnaire (TSQM) using a national panel study of chronic disease.  Health 
and Quality of Life Outcomes 2004; 2:12 
Bretz, F, Maurer, W, Brannath, W et al (2009) A graphical approach to sequentially rejective multiple 
test procedures Stat Med 28(4), 586–604. 


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FDA (2012) Guidance for industry. Suicidal Ideation and Behavior: Prospective Assessment of 
Occurrence in Clinical Trials (last draft August 2012, available under 
http://www.fda.gov/downloads/Drugs/Guidances/UCM225130.pdf) 
Gassmann-Mayer et al (2011) Clinical and statistical assessment of suicidal ideation and behavior in 
pharmaceutical trials. Clin Pharmacol Ther. 2011 Oct;90(4):554-60. 
 
Kaplan, EL, Meier, P. (1958)  Nonparametric estimation from incomplete observations. J. Amer. 
Statist. Assn. 53: 457-481. 
Keene ON, Jones MRK, Lane PW, Anderson J., et al. (2007) Analysis of exacerbation rates in asthma 
and chronic obstructive pulmonary disease: example from the TRISTAN study. Pharmaceutical 
Statistics 6: 89-97. 
Nilsson M. et al (2013) Columbia-Suicide Severity Rating Scale. Scoring and data analysis guide. 
(available at  http://www.cssrs.columbia.edu/C-
SSRS%20Scoring%20and%20Data%20Analysis%20Guide_Cross-
Industry%20Working%20Group_v2.0Final.pdf) 
Stokes ME, Davis CS, Koch GG (2000). Categorical data analysis using the SAS system. Second edition. 
SAS Institute, Inc., Cary, N.C. 
 
14 
Appendices 
 
14.1 
Appendix 1: Geographic location (state/providence and country) 
of the study centers 
Refer to clinical document CFTY720D2312 Global Qualified Sites list for study centers and their 
geographic location information. Below is the list of study centers with at least one randomized 
subject and also their region classification. 
 
Center Number 
Country 
State/Province 
Region 
 
Argentina 
CABA 
Latin American region 


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Center Number 
Country 
State/Province 
Region 
 
Argentina 
CABA 
Latin American region 
 
Brazil 
MG 
Latin American region 
 
Brazil 
RS 
Latin American region 
 
Brazil 
SC 
Latin American region 
 
Brazil 
RJ 
Latin American region 
 
Brazil 
RS 
Latin American region 
 
Brazil 
GO 
Latin American region 
 
Brazil 
SP 
Latin American region 
 
Brazil 
PR 
Latin American region 
 
CANADA 
Nova Scotia 
Northeast region 
 
CANADA 
Ontario 
Northeast region 
 
CANADA 
Alberta 
West region 
 
CANADA 
Quebec 
Northeast region 
 
CANADA 
Quebec 
Northeast region 
 
CANADA 
Quebec 
Northeast region 
 
CANADA 
British Columbia 
West region 
 
Chile 
Santiago 
Latin American region 
 
Chile 
Santiago 
Latin American region 
 
Mexico 
Chihuahua 
Latin American region 
 
Mexico 
DF 
Latin American region 
 
Mexico 
Chihuahua 
Latin American region 
 
Mexico 
Nvo Leon 
Latin American region 
 
Mexico 
Nvo Leon 
Latin American region 
 
Mexico 
Aguascalientes 
Latin American region 
 
Mexico 
San Luis Potosi 
Latin American region 
 
Mexico 
DF 
Latin American region 
 
UNITED STATES 
MI 
Midwest region 


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Center Number 
Country 
State/Province 
Region 
 
UNITED STATES 
IN 
Midwest region 
 
UNITED STATES 
FL 
Southeast region 
 
UNITED STATES 
OH 
Midwest region 
 
UNITED STATES 
FL 
Southeast region 
 
UNITED STATES 
AZ 
West region 
 
UNITED STATES 
GA 
Southeast region 
 
UNITED STATES 
NJ 
Northeast region 
 
UNITED STATES 
FL 
Southeast region 
 
UNITED STATES 
TX 
Southwest region 
 
UNITED STATES 
MI 
Midwest region 
 
UNITED STATES 
CA 
West region 
 
UNITED STATES 
OH 
Midwest region 
 
UNITED STATES 
CO 
Southwest region 
 
UNITED STATES 
OK 
Southwest region 
 
UNITED STATES 
FL 
Southeast region 
 
UNITED STATES 
NM 
Southwest region 
 
UNITED STATES 
TX 
Southwest region 
 
UNITED STATES 
IL 
Midwest region 
 
UNITED STATES 
WA 
West region 
 
UNITED STATES 
NJ 
Northeast region 
 
UNITED STATES 
NY 
Northeast region 
 
UNITED STATES 
UT 
West region 
 
UNITED STATES 
KS 
Southwest region 
 
UNITED STATES 
TN 
Southeast region 
 
UNITED STATES 
TX 
Southwest region 
 
UNITED STATES 
MI 
Midwest region 
 
UNITED STATES 
TN 
Southeast region 


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Protocol No. CFTY720D2312 
 
Center Number 
Country 
State/Province 
Region 
 
UNITED STATES 
KS 
Southwest region 
 
UNITED STATES 
VA 
Southeast region 
 
UNITED STATES 
OH 
Midwest region 
 
UNITED STATES 
IL 
Midwest region 
 
UNITED STATES 
CO 
Southwest region 
 
UNITED STATES 
NY 
Northeast region 
 
UNITED STATES 
AZ 
West region 
 
UNITED STATES 
NC 
Southeast region 
 
UNITED STATES 
OH 
Midwest region 
 
UNITED STATES 
AZ 
West region 
 
UNITED STATES 
FL 
Southeast region 
 
UNITED STATES 
TN 
Southeast region 
 
UNITED STATES 
DE 
Northeast region 
 
UNITED STATES 
FL 
Southeast region 
 
UNITED STATES 
NY 
Northeast region 
 
UNITED STATES 
CA 
West region 
 
UNITED STATES 
NY 
Northeast region 
 
UNITED STATES 
VA 
Southeast region 
 
UNITED STATES 
CO 
Southwest region 
 
UNITED STATES 
NY 
Northeast region 
 
UNITED STATES 
OK 
Southwest region 
 
UNITED STATES 
TX 
Southwest region 
 
UNITED STATES 
DC 
Northeast region 
 
UNITED STATES 
FL 
Southeast region 
 
UNITED STATES 
IL 
Midwest region 
 
UNITED STATES 
CO 
Southwest region 
 
UNITED STATES 
FL 
Southeast region 


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Center Number 
Country 
State/Province 
Region 
 
UNITED STATES 
MO 
Southwest region 
 
UNITED STATES 
NJ 
Northeast region 
 
UNITED STATES 
MO 
Southwest region 
 
UNITED STATES 
VA 
Southeast region 
 
UNITED STATES 
AL 
Southeast region 
 
UNITED STATES 
IN 
Midwest region 
 
UNITED STATES 
FL 
Southeast region 
 
UNITED STATES 
NY 
Northeast region 
 
UNITED STATES 
NC 
Southeast region 
 
UNITED STATES 
IA 
Midwest region 
 
UNITED STATES 
IL 
Midwest region 
 
UNITED STATES 
NV 
West region 
 
UNITED STATES 
OK 
Southwest region 
 
UNITED STATES 
MO 
Southwest region 
 
UNITED STATES 
OH 
Midwest region 
 
UNITED STATES 
MA 
Northeast region 
 
UNITED STATES 
MA 
Northeast region 
 
UNITED STATES 
KY 
Midwest region 
 
UNITED STATES 
OH 
Midwest region 
 
UNITED STATES 
CO 
Southwest region 
 
UNITED STATES 
PA 
Northeast region 
 
UNITED STATES 
FL 
Southeast region 
 
UNITED STATES 
TX 
Southwest region 
 
UNITED STATES 
MO 
Southwest region 
 
UNITED STATES 
CT 
Northeast region 
 
UNITED STATES 
NY 
Northeast region 
 
UNITED STATES 
TN 
Southeast region 


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Center Number 
Country 
State/Province 
Region 
 
UNITED STATES 
AZ 
West region 
 
UNITED STATES 
WA 
West region 
 
UNITED STATES 
VA 
Southeast region 
 
UNITED STATES 
MI 
Midwest region 
 
UNITED STATES 
TX 
Southwest region 
 
UNITED STATES 
FL 
Southeast region 
 
UNITED STATES 
LA 
Southeast region 
 
UNITED STATES 
SC 
Southeast region 
 
UNITED STATES 
NC 
Southeast region 
 
UNITED STATES 
MI 
Midwest region 
 
UNITED STATES 
WA 
West region 
 
UNITED STATES 
MT 
West region 
 
UNITED STATES 
PR 
Southeast region 
 
UNITED STATES 
OR 
West region 
 
UNITED STATES 
WI 
Midwest region 
 
UNITED STATES 
FL 
Southeast region 
 
UNITED STATES 
VA 
Southeast region 
 
UNITED STATES 
OH 
Midwest region