Clinical trial NCT02232061
Conditions: Multiple Sclerosis
Keywords: multiple sclerosis, fingolimod, adult, FTY720, inflammatory disease, demyelination, auto-inflammatory disease, relapsing-remitting MS, CFTY720D2406
Sponsor: Novartis Pharmaceuticals
Start date: 2014-09-29; Completion date: 2020-01-24
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate if patients who had a serious cardiovascular event upon initiation of fingolimod are at risk to delevop long term other cardiovascular events

Detailed description:
This was a multi-national, long-term safety study. Patients enrolled in study FTY720D2406 who experienced a cardiovascular event within 24-hours of fingolimod treatment initiation which led to overnight monitoring or met serious adverse event criteria, were eligible to participate in this study.

Patients who experienced a qualifying event in study CFTY720D2406 started study CFTY720D2409 approximately 6 months after the occurrence of the CFTY720D2406 qualifying event.

Patients underwent mandatory assessments on a 6-monthly basis including 12-lead ECG, vital signs. Other assessments were performed as per routine practice.

The primary objective of the study was to estimate the long-term cardiovascular risk of fingolimod in patients who experienced a cardiovascular event during treatment initiation.

The study has no stand-alone secondary objective. However data from the CFTY720D2409 and CFTY720D2406 studies will be pooled to supplement CFTY720DD2406 study and support its primary and secondary objectives of evaluating the safety profile of fingolimod.

The pooled data will be appended to this result upon completion of FDA submission.

Arms: arm 1: Fingolimod 0.5mg/day tablets taken orally.
Interventions: intervention 1: Fingolimod
Intervention descriptions: intervention 1: Fingolimod 0.5 mg tablet

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
Long-term, open-label, multicenter study assessing long-term 
cardiovascular risks in patients treated with fingolimod 
NCT Number: 
NCT02232061 
 
Document Date: 
 
Protocol Version 1: 08 August 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 


Global Clinical Development - General Medicine 
FTY720/Fingolimod 
Clinical Trial Protocol CFTY720D2409 
Long-term, open-label, multicenter study assessing long-
term cardiovascular risks in patients treated with 
fingolimod 
Authors: 
 
Document type: 
Amended protocol version (v01) Clean 
EUDRACT number: 
2014-001241-24 
Version number: 
v01 
Development phase: 
IV 
Release date: 
08-Aug-2019
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed  
without the consent of Novartis 
Template version 14-Jul-2016 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Protocol summary ................................................................................................................ 9 
Amendment 1 .................................................................................................................... 10 
1 
Introduction ....................................................................................................................... 11 
1.1 
Background ............................................................................................................ 11 
1.2 
Purpose .................................................................................................................. 12 
2 
Study objectives ................................................................................................................. 12 
2.1 
Primary objective(s) .............................................................................................. 12 
 
 13 
 
 13 
3 
Investigational plan ........................................................................................................... 13 
3.1 
Study design .......................................................................................................... 13 
3.2 
Rationale of study design ...................................................................................... 13 
3.3 
Rationale of dose/regimen and duration of treatment ........................................... 14 
3.4 
Rationale for choice of comparator ....................................................................... 14 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 14 
3.6 
Risks and benefits .................................................................................................. 14 
4 
Population .......................................................................................................................... 14 
4.1 
Inclusion criteria .................................................................................................... 15 
4.2 
Exclusion criteria ................................................................................................... 15 
5 
Treatment ........................................................................................................................... 15 
5.1 
Protocol requested treatment ................................................................................. 15 
5.1.1 
Study treatment ..................................................................................... 15 
5.1.2 
Additional study treatment .................................................................... 15 
5.2 
Treatment arms ...................................................................................................... 15 
5.3 
Treatment assignment, randomization ................................................................... 15 
5.4 
Treatment blinding ................................................................................................ 15 
5.5 
Treating the patient ................................................................................................ 15 
5.5.1 
Patient numbering ................................................................................. 15 
5.5.2 
Dispensing the study treatment ............................................................. 16 
5.5.3 
Handling of study treatment .................................................................. 16 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 16 


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5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 16 
5.5.6 
Rescue medication ................................................................................ 16 
5.5.7 
Concomitant treatment .......................................................................... 16 
5.5.8 
Prohibited Treatment ............................................................................. 16 
5.5.9 
Discontinuation of study treatment ....................................................... 17 
5.5.10 
Withdrawal of consent .......................................................................... 17 
5.5.11 
Loss to follow-up .................................................................................. 18 
5.5.12 
Emergency breaking of assigned treatment code .................................. 18 
5.5.13 
Study completion and post-study treatment .......................................... 18 
5.5.14 
Early study termination ......................................................................... 18 
6 
Visit schedule and assessments ......................................................................................... 18 
6.1 
Information to be collected on screening failures.................................................. 20 
6.2 
Patient demographics/other baseline characteristics ............................................. 20 
6.3 
Treatment exposure and compliance ..................................................................... 20 
6.4 
Effectiveness .......................................................................................................... 21 
6.5 
Safety ..................................................................................................................... 21 
6.5.1 
Physical and neurological examination ................................................. 21 
6.5.2 
Fingolimod first-dose monitoring ......................................................... 21 
6.5.3 
Vital signs.............................................................................................. 21 
6.5.4 
Height and weight ................................................................................. 21 
6.5.5 
Laboratory evaluations .......................................................................... 22 
6.5.6 
Electrocardiogram (ECG) ..................................................................... 22 
6.5.7 
Ophthalmic evaluations ......................................................................... 22 
6.5.8 
Pregnancy and assessments of fertility ................................................. 22 
6.5.9 
Appropriateness of safety measurements .............................................. 23 
6.6 
Other assessments .................................................................................................. 23 
6.6.1 
Resource utilization ............................................................................... 23 
6.6.2 
Pharmacokinetics .................................................................................. 23 
6.6.3 
Pharmacogenetics/pharmacogenomics ................................................. 23 
6.6.4 
Other biomarkers ................................................................................... 23 
7 
Safety monitoring .............................................................................................................. 23 
7.1 
Adverse events ....................................................................................................... 23 
7.2 
Serious adverse events ........................................................................................... 25 
7.2.1 
Definition of SAE ................................................................................. 25 
7.2.2 
SAE reporting........................................................................................ 26 
7.3 
Liver safety monitoring ......................................................................................... 27 


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7.4 
Renal safety monitoring ......................................................................................... 27 
7.5 
Pregnancy reporting ............................................................................................... 27 
7.6 
Prospective suicidality assessment ........................................................................ 27 
8 
Data review and database management ............................................................................. 27 
8.1 
Site monitoring ...................................................................................................... 27 
8.2 
Data collection ....................................................................................................... 28 
8.3 
Database management and quality control ............................................................ 28 
8.4 
Data Monitoring Committee .................................................................................. 28 
8.5 
Adjudication Committee ........................................................................................ 28 
9 
Data analysis ...................................................................................................................... 29 
9.1 
Analysis sets .......................................................................................................... 29 
9.2 
Patient demographics and other baseline characteristics ....................................... 29 
9.3 
Treatments ............................................................................................................. 29 
9.4 
Analysis of the primary variable(s) ....................................................................... 30 
9.4.1 
Variable(s) ............................................................................................. 30 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 30 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 30 
9.4.4 
Supportive analyses ............................................................................... 30 
 
 31 
 
 31 
 
 31 
 
 31 
 
 32 
 
 32 
 
 32 
 
 32 
9.6 
Interim analyses ..................................................................................................... 32 
9.7 
Sample size calculation ......................................................................................... 32 
10  Ethical considerations ........................................................................................................ 33 
10.1 
Regulatory and ethical compliance ........................................................................ 33 
10.2 
Informed consent procedures ................................................................................. 33 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 33 
10.4 
Publication of study protocol and results............................................................... 34 
11  Protocol adherence ............................................................................................................ 34 
11.1 
Protocol Amendments ........................................................................................... 34 
12  References ......................................................................................................................... 34 


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List of tables 
Table 5-1 
Prohibited treatment: ............................................................................. 17 
Table 6-1 
Recommended assessment schedule, including mandatory 
evaluations............................................................................................. 19 
Table 9-1 
Probability of seeing at least one serious cardiovascular event in 
D2409 .................................................................................................... 32 
 


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List of abbreviations 
ADEM 
Acute disseminated encephalomyelitis 
AE 
 
Adverse event 
ATC  
Anatomic therapeutic chemical 
CFR 
 
US code of federal regulations 
CI 
 
Confidence interval 
CNS 
 
Central nervous system 
CRA  
Clinical research associate 
CRF 
 
Case report/record form 
CRO  
Contract research organization 
DMT  
Disease modifying therapy 
DS&E  
Drug safety & epidemiology 
ECG  
Electrocardiogram 
EDC  
Electronic data capture 
EDSS  
Expanded disability status scale 
EMA  
European medicine agency 
FDA  
Food and drug administration 
GCP 
 
Good clinical practices 
HDL  
High density lipoprotein 
ICF 
 
Informed consent form 
ICH 
 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
 
Independent ethics committee 
IFN 
 
Interferon 
i.m. 
 
intra-muscular 
IN 
 
Investigator notification 
IR 
 
Incidence rate 
IRB 
 
Institutional review board 
ISS 
 
Integrated safety summary 
i.v. 
 
Intra-venous 
MedDRA 
Medical dictionary for regulatory activities 
MI 
 
Myocardial infarction 


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MS 
 
Multiple sclerosis 
OCT  
Optical coherence tomography 
PFT 
 
Pulmonary function test 
PML  
Progressive multiform leucoencephalopathy 
PPMS  
Primary progressive multiple sclerosis 
PRES  
Posterior reversible encephalopathy syndrome 
PRMS  
Progressive relapsing multiple sclerosis 
RRMS  
Relapsing remitting multiple sclerosis 
SAE 
 
Serious adverse event 
SAP 
 
Statistical analysis plan 
s.c. 
 
Sub-cutaneous 
SPMS  
Secondary progressive multiple sclerosis 
SUSAR 
Suspected unexpected serious adverse reaction 
WBC  
White blood cell 
WHO  
World health organization 
 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Enrollment 
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Protocol 
A written account of all the procedures to be followed in a trial, 
which describes all the administrative, documentation, analytical 
and clinical processes used in the trial. 
Study treatment 
Any single drug administered to the patient as part of the required 
study procedures 
Subject Number  
A number assigned to each patient who enrolls into the study  
Variable 
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study 


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Protocol summary 
 
Protocol number 
CFTY720D2409 
Title 
Long-term, open-label, multicenter study assessing long-term 
cardiovascular risks in patients treated with fingolimod 
Brief title 
Study assessing the long-term cardiovascular risks in patients treated 
with fingolimod 
Sponsor and Clinical 
Phase 
Novartis, Phase 4  
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
This study is a post-authorization follow-up measure to assess the long-
term cardiovascular risk of fingolimod in patients who experience a 
serious cardiovascular event during the first 24-hours of fingolimod 
treatment initiation in study FTY720D2406. 
Primary Objective(s) 
To estimate the long-term cardiovascular risk of fingolimod, as defined by 
the incidence of selected cardiovascular events over the course of the 
study, in patients who experienced a cardiovascular event during 
treatment initiation or re-initiation in the study D2406. 
 
 
Study design 
This is a single-arm, open-label, long-term safety study. 
Population 
The study will enroll MS patients who sustained a serious cardiovascular 
event during their fingolimod treatment initiation or re-initiation in the 
D2406 study. 
Inclusion criteria 
Patients in study D2406 who experience a cardiovascular event within 
24-hours of fingolimod treatment initiation or re-initiation having led to 
overnight monitoring or met seriousness criteria  
Exclusion criteria 
Patients receiving an investigational drug except if this is part of a 
Novartis sponsored MS study lasting less than 1 month. 
Study treatment 
Fingolimod 0.5mg/day. 
Efficacy assessments 
None  
Safety assessments 
ECG, vital signs and adverse events 
Other assessments 
None 
Data analysis 
The proportion (with 95%CI) of patients with at least one selected 
cardiovascular adverse events will be summarized.  
Results will be compared with the proportion of D2406 patients who also 
experienced a selected cardiovascular event but who did not have a 
cardiovascular event during the first 24 hours after initiation of fingolimod 
treatment in D2406. 
Key words 
Long-term cardiovascular risks, fingolimod, MS 


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Amendment 1 
Amendment rationale 
Amendment 1 to protocol CFTY720D2409 is developed to align with the recent safety related 
updates  to the Fingolimod label (SmPC) and to introduce administrative changes in the 
protocol to align with the language of D2406, the parent study from which patients are being 
enrolled into D2409 study.   
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlining for insertions. 
The changes applied are the following: 
 Discontinuation section (5.5.9) has been updated to warn about the potential occurrence of 
severe exacerbation of disease upon fingolimod discontinuation. 
 Pregnancy section (6.5.8) has been updated to inform about the contraindication in 
pregnancy (and in women of child bearing potential not applying highly effective 
measures of contraception) recently added to the SmPC 
 
 
  
 Clarification that First Dose Monitoring events qualifying for participation in 
FTY720D2406 can be considered during initiation or re-initiating of Fingolimod treatment  
 Clarification that ECG reading should be done by a qualified physician 
 Other minor editorial changes. 
 


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1 
Introduction 
1.1 
Background 
Multiple Sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system 
characterized by inflammation, demyelination and axonal/neuronal destruction, ultimately 
leading to severe disability. MS affects ~ 2.5 million individuals worldwide. At diagnosis, 
approximately 85% of patients have relapsing-remitting MS (RRMS), characterized by 
recurrent, acute episodes (relapses) of neurological symptoms. After 6-10 years, 30-40% of 
patients with RRMS have progressed to secondary progressive MS (SPMS), when a less 
inflammatory, and more neurodegenerative, course of disease takes precedence. SPMS can 
also be segregated based on whether patients continue to experience relapses (relapsing form 
of SPMS) or not (purely progressive SPMS). About 10-15% of MS patients present with a 
primary progressive course (PPMS) defined by a continuous accumulation of neurological 
disability from symptom onset without superimposed exacerbations or remissions. 
Progressive relapsing MS (PRMS; chronic progressive from onset with infrequent relapses) is 
the least frequent form of MS.  
Several therapies are approved for patients with RRMS and fall within 8 classes of products: 
interferon (IFN) (1a and 1b), glatiramer acetate (amino acid copolymer), natalizumab 
(selective adhesion molecule inhibitor), mitoxantrone (chemotherapeutic), fingolimod (S1P 
receptor modulator), teriflunomide (pyrimidine synthesis inhibitor), dimethylfumarate 
(fumarates) and alemtuzumab (anti-CD52). All are considered as immunomodulatory or 
immunosuppressive medications. Beta interferons have multiple immune actions but the 
means by which the drugs are effective in MS remains unknown. They have shown modest 
(~30%) effect on relapses and in the case of IFN-1a, on disability (Goodin et al. 2002). 
Relatively minor differences in efficacy, based on dose frequency, exist between IFN 
products. Glatiramer acetate, a random mixture of amino acid copolymers has an effect on 
relapses similar to IFN- but has not shown an effect on disability (Goodin et al. 2002). 
Natalizumab blocks lymphocyte migration into the CNS by inhibiting interaction of alpha-4 
integrins on lymphocytes with the endothelial receptor VCAM-1 leading to significant 
reductions in relapse rate (68%) and disability (42%) (Polman et al. 2006). The risk of 
progressive multiform leucoencephalopathy (PML) limits use of this product predominantly 
to second-line situations (Ransohoff, 2007). Whether patients negative for antibodies to the JC 
virus (causal agent of PML) will have a lower risk of PML than those positive for antibodies 
(as appears likely based on preliminary reports) remains to be determined. Likewise, 
mitoxantrone, a chemotherapeutic agent, while demonstrating efficacy on relapses, is 
associated with risks of cardiac and hematological events that substantially restrict its use 
(Goodin et al. 2002). Interferon, glatiramer acetate, natalizumab and alemtuzumab are given 
by injection (SC, IM or IV) whereas fingolimod, teriflunomide and dimethylfumarate are oral 
medications. 
Fingolimod (FTY720) 0.5 mg is an oral drug which has been approved in 90 countries for 
treatment of patients with relapsing of MS. Fingolimod 0.5 mg is an effective therapy to 
reduce the risk of relapses in patients with relapsing forms of MS. 


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The safety profile of fingolimod has been well characterized with over 284,000 MS patients 
treated with fingolimod in the context on clinical studies and in the post-marketing setting, 
comprising over 677,779 patient years of exposure by 31-May-2019.  
Upon initiation of fingolimod there is activation of the S1P1 receptor that leads to transient 
negative chronotropy and dromotropy, which are the basis for the monitoring of heart rate and 
BP required for at least six hours upon the initiation of fingolimod. The incidence of 
bradyarrhythmic events and intolerance of these events that requires additional monitoring is 
infrequent. Whether or not such events within the first day of the initiation of fingolimod in 
MS patients have any association with long term risk for major adverse cardiovascular events 
is unknown. 
As part of an EMA post-authorization follow-up measure and an FDA post-approval 
commitment a large observational post-authorization safety study CFTY720D2406 (D2406) is 
being conducted in several countries. This study will provide important information on the 
usage and the safety profile of fingolimod in a real life setting. However given its 
observational nature it does not allow to mandate procedures (e.g. ECG) which would be 
needed in order to properly evaluate whether or not serious cardiovascular events following 
fingolimod initiation have any association with long-term risk for serious cardiovascular 
events. Therefore the current study (D2409) is being implemented. This study will be 
conducted in D2406 patients who experienced such cardiovascular events. It will complement 
D2406 study by collecting all data in a similar manner as the D2406 study in addition to some 
extra mandated examinations.  
For the purpose of this protocol, the term “fingolimod initiation” is used for first initiation as 
well as for re-initiation following fingolimod treatment interruption. 
1.2 
Purpose  
This study is an additional EMA post-authorization follow-up measure to assess the 
cardiovascular risk of fingolimod in those patients who experience a cardiovascular event 
during the first 24-hours of fingolimod treatment initiation in study D2406 which leads to 
overnight monitoring or meets seriousness criteria. 
In addition, this study will also explore the overall safety profile of fingolimod under 
conditions of routine medical practice as in protocol D2406. 
2 
Study objectives 
2.1 
Primary objective(s) 
To estimate the long-term cardiovascular risk of fingolimod in patients who experienced a 
cardiovascular event during treatment initiation, as defined by the incidence of selected 
cardiovascular events over the course of the study. 


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3 
Investigational plan 
3.1 
Study design 
This is a multi-national, long-term safety study. Patients enrolled in study D2406 who 
experienced a cardiovascular event within 24-hours of fingolimod treatment initiation which 
led to overnight monitoring or met serious adverse event criteria, are eligible to participate in 
this study.  
Patients eligible and consenting to study D2409 will discontinue their study D2406 
participation and be followed in study D2409. Study D2409 enrollment period will be open 
until 1-year before the end of study D2406 and the study will last until the end of Study 
D2406 i.e. five years after the last patient has been enrolled in Study D2406. 
Patients who experience a qualifying event in study D2406 should start study D2409 
approximately 6 months after the occurrence of the D2406 qualifying event or as soon as 
possible after the site initiation. 
As part of this study, patients will undergo mandatory assessments on a 6-monthly basis 
including 12-lead ECG, vital signs and a check list for the occurrence of selected events. 
Other assessments will be performed as per routine practice. 
During the course of the study, patients switching to another MS therapy will remain in the 
study provided they fulfill the criteria defined in Section 5.5.9. These patients will have their 
last mandated evaluations 6 months after the discontinuation of fingolimod (see Table 6-1). 
After this time point, they will be followed according to routine practice without additional 
mandatory assessments. 
3.2 
Rationale of study design 
This study is designed to assess the long-term cardiovascular risk of fingolimod in patients 
who experienced a cardiovascular event during fingolimod treatment initiation. As study 
D2406 provides a real-life population treated with fingolimod and allows easy identification 
and enrollment of patients, it was selected as the source of patients for D2409 study. 


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The data collection will be aligned to the study D2406 protocol apart from additional 
cardiovascular data in order to facilitate data pooling as well as to allow study D2406 patients 
who did not have any such first-dose event to be used as the comparator to study D2409 
patients.  
3.3 
Rationale of dose/regimen and duration of treatment 
Fingolimod 0.5 mg/day is the dose approved for the indication of relapsing forms of MS. The 
prescription of fingolimod, as well as the decision to discontinue treatment are at the sole 
discretion of the prescribing physicians and the patients and are not part of the study plan.  
Patients will have different duration of follow-up based on when they join the study. Patients 
will be followed until 5 years after the last patient has been enrolled in Study D2406. 
3.4 
Rationale for choice of comparator 
There is no comparator group enrolled in this study. Comparison will be made using 
fingolimod patients enrolled in Study D2406 who did not have any first-dose cardiovascular 
event as they provide a reasonable cohort with similar baseline data collection and allow an 
estimation of the risk of selected cardiovascular events. 
3.5 
Purpose and timing of interim analyses/design adaptations 
A descriptive summary of the data of this study will be compiled on a periodic basis (at least 
yearly) in a pooled manner with data from Study D2406. 
3.6 
Risks and benefits  
The safety profile of fingolimod has been well characterized with over 284,000 MS patients 
treated with fingolimod in the context of clinical studies and in the post-marketing setting, 
comprising over 677,779 patient years of exposure by 31-May-2019. During the course of the 
fingolimod clinical development, several areas were identified as safety areas of note: 
bradyarrhythmias upon treatment initiation, liver transaminase elevations, hypertension and 
macular edema; additional safety areas of interest include infections, malignancies and 
reproductive toxicity. 
All risks related to fingolimod or other MS DMTs are described in the respective patient 
information leaflets. 
Given that the treatment decision is independent from study participation, the additional risk 
for subjects to participate in this study is limited to the added procedures (i.e. a 6-monthly 
ECG) for which no risk is foreseen. 
4 
Population 
This study will include patients with relapsing forms of MS who have been prescribed 
treatment with fingolimod by their treating physician as part of their MS treatment in 
accordance with the routine clinical practice and who in the context of the study D2406 
experienced certain cardiovascular events during their fingolimod initiation. 


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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. Patient experienced a cardiovascular event within 24-hours of fingolimod treatment 
initiation or re-initiation which led to overnight monitoring or met seriousness criteria 
3. Patient experienced this cardiovascular event while participating in the study 
CFTY720D2406  
4. Patient continues receiving fingolimod after the first dose event 
4.2 
Exclusion criteria 
Patients treated with any investigational drug unless it is received as part of a Novartis 
sponsored MS study lasting less than 1 month. 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Study treatment 
The study treatment is fingolimod. 
Novartis will provide fingolimod 0.5 mg capsules supplies locally for the duration of the 
study participation according to if required by local regulations. Otherwise, local 
commercially available supplies will be used. Novartis will not provide any other MS 
treatment to patients who may discontinue fingolimod prior to the study end. 
5.1.2 
Additional study treatment 
No additional treatment is requested for this trial. 
5.2 
Treatment arms 
There is only one treatment arm with patients receiving fingolimod 0.5mg/day. 
5.3 
Treatment assignment, randomization 
Not applicable. 
5.4 
Treatment blinding  
Not applicable. 
5.5 
Treating the patient  
5.5.1 
Patient numbering  
Each patient will retain the numbering they had in the study D2406.  


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5.5.2 
Dispensing the study treatment  
Each study site will be supplied if required by local regulations. Otherwise, local 
commercially available supplies will be used. 
5.5.3 
Handling of study treatment  
5.5.3.1 
Handling of study treatment  
Study treatment will be handled as per local procedures. 
5.5.3.2 
Handling of other study treatment  
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment  
All dose changes during the study must be recorded on the MS disease modifying therapy 
records eCRF. 
The investigator should promote compliance by instructing the patient to take the study 
treatment exactly as prescribed. The patient should be instructed to contact the investigator if 
he/she is unable for any reason to take the study treatment as prescribed. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
Study treatment dose adjustments and/or interruptions are permitted as per investigator 
judgment. 
These changes must be recorded on the MS disease modifying therapy records eCRF. 
5.5.6 
Rescue medication  
Not applicable. 
5.5.7 
Concomitant treatment  
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after being enrolled into the study. All medications, procedures and significant 
non-drug therapies (including physical therapy and blood transfusions) administered after the 
patient was enrolled into the study must be recorded Concomitant Medications eCRF. 
5.5.8 
Prohibited Treatment  
During the course of the study, if a patient switches to an unapproved MS DMT (i.e. marketed 
drug used as MS DMT without however being approved for MS indication), this patient will 
have to stop study participation. If possible, data should then be captured at the time of this 
change in MS therapy independently of the 6-monthly protocol scheduled visit and 6 months 
later. This last time point will constitute the end-of-study data collection point for this patient. 
Patients who start treatment with any investigational drug (MS DMT or not) will have to stop 
the study participation from the day they start this investigational drug. 


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Table 5-1 
Prohibited treatment: 
Medication 
Action to be taken 
Unapproved MS DMT 
Discontinuation from  study 6 months after the end of the 
approved MS DMT 
Investigational drugs 
Discontinuation from study on the day investigational drug is 
started 
5.5.9 
Discontinuation of study treatment  
During the course of the study, a patient may discontinue fingolimod: 
 If this patient then starts another approved MS DMT or does not start any DMT at all (i.e. 
remains off DMT), he/she remains in the study. If possible, data should then be captured 
at the time of this change in MS therapy (either to another DMT or stopping DMTs 
entirely), 6 months later and thereafter as per the recommended data collection schedule 
until the end of the study (see Table 6-1).  
 If this patient switches to an unapproved MS DMT, this patient will have to stop study 
participation as described above in Section 5.5.8. 
Patients may voluntarily discontinue study treatment for any reason at any time.  
The investigator should discontinue study treatment for a given patient if he/she believes that 
continuation would be detrimental to the patient’s well-being. 
Cases of severe exacerbation of the disease have been reported after discontinuation of 
fingolimod in the post-marketing setting. These cases were generally observed within 12 
weeks after stopping fingolimod, but in some cases up to 24 weeks after Gilenya 
discontinuation. Therefore, caution is indicated when stopping Gilenya therapy. If 
discontinuation of Gilenya is deemed necessary, patients should be monitored for relevant 
signs and symptoms and appropriate treatment should be initiated as required. 
5.5.10 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.  
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study related contacts. 
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information in 
accordance with local regulations. Upon withdrawal of study participation, study treatment 
(i.e. fingolimod) will no longer be supplied and the patient will return to the prescribed 
medication as decided together with the treating physician. For patients visiting their sites 
infrequently, the site staff should contact the patient by phone at least once per year until 
study completion to collect his/her vital status (i.e. dead or alive, occurrence of SAEs and any 
change in MS treatment. See also section 5.5.9 


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5.5.11 
Loss to follow-up  
For 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 contacting the 
patient, family or family physician as agreed in the informed consent and by documenting in 
the source documents steps taken to contact the patient. The treating physician should try to 
contact the patient or one of his/her relatives or the general practitioner (if such is known) in 
order to collect the patient’s vital status, including when applicable, the cause of death. 
If, despite three attempts spread over a 6-month period using different modalities (e.g. phone, 
fax, registered receipt letter), the treating physician is not successful in making contact with 
the patient, the patient will be considered lost to follow-up. Patients will be considered lost to 
follow-up from the date of the last successful contact. 
5.5.12 
Emergency breaking of assigned treatment code  
Not applicable. 
5.5.13 
Study completion and post-study treatment  
The study will be considered completed five years after the enrollment of the last patient in 
the study D2406. 
A patient is considered to have completed the study when he/she will have been followed 
until that time-point.  
The study might be prematurely terminated for several reasons see Section 5.5.14. 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
5.5.14 
Early study termination  
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
study patients should be seen as soon as possible. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the patient’s interests. The investigator will be responsible for informing the 
Institutional Review Board/Independent Ethics Committee (IRBs/IECs) of the early 
termination of the trial. 
6 
Visit schedule and assessments 
As part of this study, patients will have mandatory assessments on a 6-monthly basis (i.e. 
ECG and vital signs) as long as they are treated with fingolimod and up to 6 months after a 
potential fingolimod permanent discontinuation. Frequency and nature of other data will be 
captured as per routine practice as described below in Table 6-1.  
The study entry visit should be scheduled approximately 6 months after the patient 
experienced his/her cardiovascular event in the study D2406.  


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At this visit the patient will sign the Study D2409 informed consent and any new data 
pertaining to this patient will need to be captured in the D2409 eCRF. The end of Study 
D2406 will be on the day Study D2409 informed consent is signed. 
For patients who experienced this qualifying event more than 6 months prior to Study D2409 
implementation at the site, the study entry visit should be scheduled as soon as possible after 
site initiation. 
The study recommends a visit window of +/- 1 month for all mandatory evaluations. 
In the study eCRF, fingolimod discontinuation and 6-month follow-up time-points will be 
documented under routine study visits. 
Table 6-1 
Recommended assessment schedule, including mandatory 
evaluations 
Visit/ study time-points Study entry 
visit  
 
Routine 
study visit 
(Every 6 
months)  
Fingolimod 
discontinuation8  
6-
months 
fup9 
Abbreviated 
Routine 
visit10 
End of 
study  
Assessments and data 
collection page 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X11 
12-lead ECG 
X 
X 
X 
X 
 
X11 
Selected Adverse 
Events1 
X 
X 
X 
X 
X 
X11 
MS status2 
X 
X 
X 
X 
X 
X 
Laboratory results3 
X 
Record as needed 
Ophthalmic 
examination4 
Record as needed 
1st dose observation5 
Record as needed 
Pregnancy status 
(female of childbearing 
potential only)  
Record as needed 
Dermatological 
examination 
Record as needed 
Additional 
examination6 
Record as needed 
Adverse events7 
Record as needed 
Serious Adverse 
Events7 
Record as needed 
MS disease-modifying 
therapy record 
X 
Record as needed 
Concomitant 
medication 
Record as needed 
Study completion 
 
 
 
 
 
X 
Bold denotes mandatory evaluations 
1  Selected AEs include cardiac and vascular events (e.g. stroke, myocardial infarction, angina pectoris and peripheral 


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Visit/ study time-points Study entry 
visit  
 
Routine 
study visit 
(Every 6 
months)  
Fingolimod 
discontinuation8  
6-
months 
fup9 
Abbreviated 
Routine 
visit10 
End of 
study  
Assessments and data 
collection page 
 
 
 
 
 
 
vascular disease, second and third degree AV block, hypertension), symptomatic bradyarrhythmias on treatment initiation or 
on re-starting after an interruption in fingolimod therapy, eye events (e.g. macular edema), liver events, any infection, 
pulmonary events (e.g. dyspnea, asthma), malignancies (e.g. lymphoma), seizures, atypical MS relapse, other atypical 
severe neurological events (e.g. ADEM, PRES) and sudden/unexplained death. 
2. MS status will capture when available, MS relapses, EDSS. 
3. i) If total and HDL-cholesterol results were not collected as part of the D2406 baseline laboratory results, a sample will 
need to be drawn and analyzed for these 2 parameters. This is the only mandatory laboratory evaluation required for this 
study. ii) Only local laboratory results are being captured. Results of lymphocyte count, total WBC count and liver function 
tests whether normal or abnormal should be captured systematically in the CRF, whenever available.  Other laboratory 
parameter results are to be captured when considered clinically relevant (whether abnormal or not). For ischemic type of 
events, results of prothrombin time/partial thromboplastin time, homocysteine, Activated protein C Resistance, lupus 
anticoagulant, antiphospholipid antibody, protein C, protein S fibrinogen and antithrombin III should be collected if performed. 
4. Ophthalmic evaluation will capture, when available, visual acuity and macular edema status. 
5. To be documented only for patients who re-start fingolimod after an interruption of dosing. 
6. Additional examination (e.g. Chest X-Ray, PFT, Echocardiography…) performed in order to characterize an adverse event 
should be documented.  
7. All events meeting the criteria for an AE or SAE should be reported on the “Adverse events” eCRF page. 
8. Any evaluation performed at the time stopping fingolimod should be documented. 
9. Patients who stopped fingolimod and switched to another approved MS DMT will have the 6 month follow-up visit with the 
mandatory ECG.  
10. Patients discontinuing fingolimod will remain in the study. Only data captured per routine practice will reported. See 
Section 5.5.9 
11. Evaluations are mandatory for patients still on fingolimod at the time of the study completion. These are not mandatory for 
patients who stopped fingolimod prior to this time-point. 
6.1 
Information to be collected on screening failures  
Not applicable. 
6.2 
Patient demographics/other baseline characteristics  
Patient demographics, baseline laboratory results, medical history in particular cardiac 
medical history and fingolimod first-dose-monitoring data will be captured as part of the 
study D2406 eCRF. 
Data required to calculate the Framingham Point Score for 10-Year risk for coronary heart 
disease as well as the European cardiovascular risk score will be collected at study entry visit 
if they were not already captured in study D2406. These are age, gender, smoking status, 
systolic blood pressure and total & HDL cholesterol. 
6.3 
Treatment exposure and compliance  
Although it is expected that patients will receive fingolimod 0.5 mg daily per local prescribing 
information, it is recognized that in a clinical setting, dosing may be delayed or interrupted 
due to personal reasons, physical reasons, physical conditions, or co-morbidities.  Any change 
in fingolimod treatment (e.g. interruption, change in dose or change in drug) and the reason 
for change should be documented in the MS treatment eCRF. This will allow measurement of 
treatment compliance. 


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6.4 
Effectiveness 
In order to document the disease evolution of the study population, MS status including 
number of relapses and EDSS, should be collected whenever available. 
6.5 
Safety 
The following information should be collected in the context of this study in line with the 
different local label recommendations and whenever available:  
 Physical and neurological examination findings, together with the occurrence of selected 
adverse events 
 Fingolimod first dose monitoring data  
 Vital signs  
 ECG 
 Laboratory evaluations results  
 Ophthalmologic examinations results  
 Dermatological examination result 
 Other examination (e.g. Chest X-ray, Pulmonary function test…) 
6.5.1 
Physical and neurological examination  
A physical examination may be performed at a routine clinical visit and may include an 
assessment of skin, head and neck, lymph nodes, breast, heart, lungs, abdomen, back and/or 
comments on general appearance. A neurological examination may also be a part of the 
physical examination. Significant findings that occur during the study which meet the 
definition of an AE as defined per this protocol (see Section 7.1 ) should be recorded on the 
Adverse Event eCRF. 
6.5.2 
Fingolimod first-dose monitoring 
For any patient stopping and re-starting fingolimod, first-dose monitoring should be fully 
documented in the eCRF for each patient (e.g. vital signs, ECG, documentation in any event if 
available). 
6.5.3 
Vital signs  
Vital signs are to be recorded at each half-year visit as long as the patient is on fingolimod 
therapy and if applicable, 6 months after discontinuation from fingolimod. After this time-
point, vital signs may be recorded at routine clinical visits. Vital signs may include sitting 
pulse rate, sitting systolic and diastolic blood pressure. 
6.5.4 
Height and weight  
Body weight may be recorded at each routine clinical visit while height is collected in study 
D2406 and will not be collected again in study D2409. 


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6.5.5 
Laboratory evaluations 
Patients for whom total and HDL-cholesterol results were not collected at the time of the 
study D2406 baseline will need to have a sample drawn and analyzed. Results will be 
collected in the eCRF. 
All available results for lymphocyte counts, total WBC counts, and liver function tests, 
whether or not clinically significant should be recorded.  
Additionally, results from tests performed to characterize an adverse event should be collected 
to properly document the event irrespective of normal or abnormal. This might include but is 
not limited to a complete white blood cell differential count or antibody titers for serious 
infections. 
In this context, in case of ischemic type of events, results of prothrombin time/partial 
thromboplastin time, homocysteine, Activated protein C Resistance, lupus anticoagulant, 
antiphospholipid antibody, protein C, protein S fibrinogen and antithrombin III should also be 
recorded if available. 
6.5.6 
Electrocardiogram (ECG)  
A standard 12-lead ECG will be performed on a 6-monthly basis. Interpretation of the tracing 
shall be made by a qualified physician and documented on the ECG section of the eCRF. 
Each ECG tracing should be labeled with the study number, patient number, date, and kept in 
the source documents at the study site. 
Clinically significant abnormalities should be recorded on the relevant section of the AE 
eCRF page as appropriate. 
6.5.7 
Ophthalmic evaluations 
Any ophthalmic evaluations performed as part of routine clinical practice, should be recorded. 
Ophthalmic evaluation may include but is not limited to fundoscopy, visual acuity and OCT, 
if needed. Ophthalmic examinations should be performed according to the local label for the 
purpose of detecting macular edema.  
6.5.8 
Pregnancy and assessments of fertility  
According to the updated SmPC, Fingolimod is contraindicated for pregnant women and 
women of childbearing potential (WOCBP) not using effective contraception. Females who 
are pregnant or nursing a child cannot participate in this trial. It must be confirmed that the 
subject is not pregnant at the time of study entry.  
For a female patient of childbearing potential, defined as physiologically capable of becoming 
pregnant, participating in the study, it is mandatory for them to use an appropriate form of 
birth control. Contraception is required as described below. These highly effective methods of 
birth control have a less than 1% chance of unwanted pregnancy during one year, if used 
appropriately according to the instructions of the manufacturer. 
 Use of a combination of any two of the following (a+b or a+c or b+c): 


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a. 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 (in case of oral 
contraception you should have been using the same pill on a stable dose for a minimum 
of 3 months before taking study treatment), 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS), 
c. Use of an occlusive cap (diaphragm or cervical/vault cap) by you, or a condom by your 
male partner combined with a spermicidal foam/gel/film/cream/vaginal suppository. 
Since it takes approximately 2 months to eliminate fingolimod from the body after stopping 
treatment, a potential risk to the fetus may persist and contraception should be pursued for 2 
months after finishing study treatment.  
If WOCBP becomes pregnant during the study while being treated with fingolimod, they must 
discontinue the treatment and shall immediately inform the treating physician to discuss 
management options. In addition, the event should be reported as per Section 7.5. 
6.5.9 
Appropriateness of safety measurements  
The safety measurements collected in this study were selected based on actual or potential 
signals identified as part of the fingolimod clinical development program as well as the risk 
management plan. 
6.6 
Other assessments 
There is no other assessment performed in the context of this study. 
6.6.1 
Resource utilization  
Not applicable. 
6.6.2 
Pharmacokinetics  
Not applicable. 
6.6.3 
Pharmacogenetics/pharmacogenomics  
Not applicable. 
6.6.4 
Other biomarkers  
Not applicable. 
7 
Safety monitoring  
7.1 
Adverse events  
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 


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study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal product. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory tests, or 
other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
 they induce clinical signs or symptoms,  
 they are considered clinically significant,  
 they require therapy.  
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes, or 
values which are considered to be non-typical in patient with underlying disease. Investigators 
have the responsibility for managing the safety of individual patient and identifying adverse 
events. 
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information. 
 the severity grade 
 mild: usually transient in nature and generally not interfering with normal activities 
 moderate: sufficiently discomforting to interfere with normal activities 
 severe: prevents normal activities 
 its relationship to the study treatment 
 its duration (start and end dates) 
 whether it constitutes a serious adverse event (SAE - see Section 7.2 for definition of 
SAE) 
 action taken regarding study treatment  
All adverse events should be treated appropriately. Treatment may include one or more of the 
following:  
 no action taken (i.e. further observation only)  
 study treatment dosage adjusted/temporarily interrupted  
 study treatment permanently discontinued due to this adverse event  
 concomitant medication given  
 non-drug therapy given  
 patient hospitalized/patient’s hospitalization prolonged  
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 


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necessary) of any changes in severity, the suspected relationship to the study drug and the 
interventions required to treat it. 
Information about common side effects already known about the study treatment can be found 
in the respective patient information leaflets. Investigators should inform study patients at the 
most nearest subsequent protocol visit about most updated safety information (adverse drug 
reaction) updated in the local label. 
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
7.2 
Serious adverse events 
7.2.1 
Definition of SAE  
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria: 
 is fatal or life-threatening  
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (e.g. hospitalization for relapse treatment) 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
 social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
 is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 


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Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured on the eCRF, SAEs also require individual 
reporting to DS&E as per Section 7.2.2. 
7.2.2 
SAE reporting  
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 12 weeks after the patient has stopped study participation 
(defined as time of last visit) must be reported to Novartis within 24 hours of learning of its 
occurrence. Any SAEs experienced after the 12 weeks period should only be reported to 
Novartis if the investigator suspects a causal relationship to study treatment.  
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to the study treatment, complete the SAE Report Form in English, and send the 
completed, signed form by fax within 24 hours after awareness of the SAE to the local 
Novartis Drug Safety and Epidemiology Department. The telephone and fax number of the 
contact persons in the local department of Drug Safety and Epidemiology, specific to the site, 
are listed in the investigator folder provided to each site. The original copy of the SAE Report 
Form and the fax confirmation sheet must be kept with the case report form documentation at 
the study site. Follow-up information should be provided using a new paper SAE Report 
Form stating that this is a follow-up to a previously reported SAE. 
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is not previously documented in the Package Insert (new occurrence) and is 
thought to be related to the study treatment a Drug Safety and Epidemiology Department 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries. 


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7.3 
Liver safety monitoring  
Not applicable 
7.4 
Renal safety monitoring  
Not applicable 
7.5 
Pregnancy reporting  
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
7.6 
Prospective suicidality assessment 
Not applicable. 
8 
Data review and database management  
8.1 
Site monitoring 
Before study initiation, at a site initiation visit, a Novartis representative will review the 
protocol and CRFs with the investigators and their staff. During the study, Novartis employs 
several methods of ensuring protocol and GCP compliance and the quality/integrity of the 
sites’ data. The field monitor will visit the site to check the completeness of patient records, 
the accuracy of entries on the eCRFs, the adherence to the protocol and to Good Clinical 
Practice. Key study personnel must be available to assist the field monitor during these visits.  
Continuous remote monitoring of each site’s data may be performed by a centralized Novartis 
CRA organization. Additionally, a central analytics organization may analyze data & identify 
risks & trends for site operational parameters, and provide reports to Novartis Clinical Teams 
to assist with trial oversight. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on 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). 


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The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed. 
8.2 
Data collection  
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to US CFR 21Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.  
8.3 
Database management and quality control  
Novartis staff and a CRO working on behalf of Novartis review the data entered into the 
CRFs by investigational staff for completeness and accuracy and instruct the site personnel to 
make any required corrections or additions. Queries are sent to the investigational site using 
an electronic data query. Designated investigator site staff is required to respond to the query 
and confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff that will make the correction to the database. The signed copy of the 
Data Query Form is kept at the investigator site. 
Medications entered into the database will be coded using the WHO Drug Reference List, 
which employs the Anatomical Therapeutic Chemical classification system. Concomitant 
procedures, non-drug therapies and adverse events will be coded using the Medical dictionary 
for regulatory activities (MedDRA) terminology. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and made available for data analysis. Any changes to the database after that time can 
only be made after written agreement by Novartis Development management. 
8.4 
Data Monitoring Committee 
Not required. 
8.5 
Adjudication Committee  
Not required. 


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9 
Data analysis  
This section describes the analyses which will be performed to specifically address the study 
D2409 objectives. In addition all data from studies D2406 and D2409 will be analyzed and 
summarized in a pooled manner. These analyses are described as part of the study D2406 
protocol and are not always repeated here. 
The purpose of this study is to estimate the long-term cardiovascular risk of fingolimod in 
patients who sustained a significant cardiovascular event during treatment initiation in study 
D2406. Descriptive summary statistics (incidence and incidence rates, with respective 95% 
confidence intervals (CI)) will be generated when applicable and be included in the annual 
periodic safety updates that are required by the health authorities. 
9.1 
Analysis sets  
The D2409 Safety set will consist of all patients who signed Study D2409 informed consent. 
9.2 
Patient demographics and other baseline characteristics  
Patient demographic and baseline characteristics, as recorded in the Study D2406 database, 
will be summarized for the D2409 Safety set. 
Patient demographic and baseline characteristic data will be described by means of absolute 
and relative frequencies for categorical variables and mean, standard deviation, minimum and 
maximum for continuous variables. Categorical variables will include sex, race, ethnicity, 
country, year of birth (grouped) and age. Continuous variables will include age, height and 
weight. 
In addition, Framingham score as well as the European cardiovascular risk score will be 
summarized separately for D2409 Safety set, and for the D2406 fingolimod patients who did 
not experience a cardiovascular event during treatment initiation. 
Relevant medical history/current medical condition data; MS history and MS treatment data 
will also be summarized by frequency of such conditions and treatments. Duration of MS and 
duration of previous MS treatment at D2406 study entry will be described with mean, median, 
standard deviation, minimum and maximum. 
9.3 
Treatments  
Overall exposure to treatments will be presented for the D2409 Safety set. 
Duration of exposure the study treatment is the number of days from the day of first dose at or 
after D2406 study entry until the last day of this treatment in the D2409 study. The days when 
the patient did not take any treatment of interest will be excluded, i.e. duration of exposure 
will exclude periods of temporary interruption of treatment.  
Patients will be considered as being on continuous fingolimod therapy if their fingolimod 
treatment interruption is less than 45 consecutive days. 
Duration of exposure to the study treatment will be described with mean, standard deviation, 
minimum and maximum. Frequency and percentage of patients exposed for a minimum 


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duration (i.e.  1 week, 1 month, 3 months, 6 months, etc.) will be reported along with the 
summary statistics of duration of exposure. 
Percentage of patients discontinuing fingolimod as well as the reason for discontinuation will 
be reported. 
Concomitant medications/significant non-drug therapies will be summarized by ATC code 
and preferred term. 
9.4 
Analysis of the primary variable(s) 
The primary objective is to estimate the long-term cardiovascular risk, as measured by the 
proportion of patients experiencing at least one selected cardiovascular event, in patients with 
long-term exposure to fingolimod once they have been identified as being at risk during 
treatment initiation in study D2406. 
9.4.1 
Variable(s) 
The primary variable will be the proportion of patients in the D2409 Safety Set who 
experienced at least one selected cardiovascular events. 
Selected cardiovascular events include, but are not limited to, sudden unexplained death, 
cardiovascular death, myocardial infarction (MI), Q-wave MI, stroke (ischemic or 
hemorrhagic), unstable angina requiring hospitalization, congestive heart failure requiring 
hospitalization, complete heart block, ventricular fibrillation, torsade de pointes, hypertensive 
emergency and any other suspected life threatening cardiovascular condition. An exhaustive 
list of MedDRA preferred terms will be part of the analysis plan.  
9.4.2 
Statistical model, hypothesis, and method of analysis 
The proportion of patients with at least one selected cardiovascular adverse events post 
treatment initiation will be summarized for the D2409 Safety Set. Corresponding exact 95% 
confidence interval (Clopper-Pearson 1934) will be calculated.  
9.4.3 
Handling of missing values/censoring/discontinuations 
Reasonable attempts should be made to limit the amount of missing data related to safety and 
patient outcomes to ensure that important information related to the primary objective of the 
study, evaluation of the long-term safety of fingolimod, is captured.  No imputation will be 
made on the eCRFs for missing data and further details of how missing data will be handled 
will be outlined in the SAP. 
9.4.4 
Supportive analyses  
In order to put the D2409 data into perspective, a comparison will be made with the patients 
in D2406 who did not experience a D2409 qualifying event. Specifically, the proportion of 
patients in this latter subset who subsequently experience at least one selected cardiovascular 
adverse events will be summarized along with corresponding exact 95% confidence interval 
(Clopper-Pearson 1934) and compared with that of D2409.  


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Furthermore, matching techniques will be used to identify a sample from the other DMT 
cohort in the D2406 study which shares same background cardiac risk as the D2409 patients. 
Background variables used in the matching will include the Framingham score (10 year risk) 
for cardiovascular disease. The proportion of patients experiencing at least one selected 
cardiovascular adverse events post treatment initiation will be summarized for this matched 
sample, along with corresponding exact 95% confidence interval (Clopper-Pearson). 
 
 
 
 
 
 
 
 


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9.6 
Interim analyses  
Interim reports will be generated yearly according to reporting requirements using data pooled 
from D2406 and D2409 studies. The enrolment numbers, baseline characteristics of patients 
as well as incidence of events reported will be described in a pooled manner. 
9.7 
Sample size calculation 
There is no sample size calculation since patient number will be driven by the proportion of 
fingolimod patients in D2406 study experiencing a cardiovascular event during treatment 
initiation which leads to overnight monitoring or meets seriousness criteria, and consenting to 
participate into this D2409 study. Based on observed incidence of such cardiovascular event 
occurring during the fingolimod first initiation in the clinical trial setting (1.4% based on 
patients from ISS January 2012 submission, Group D and Group E), it is estimated that 
approximately 40 patients may be enrolled in this study. 
This small sample size and its associated power constitute the limitation to this study. 
Table 9-1 provides the operating characteristics of this study based on a sample size of 40 
patients, that is, it gives the probability of seeing at least one selected cardiovascular event in 
the D2409 study, for a range of a priori true proportions.  
Table 9-1 
Probability of seeing at least one serious cardiovascular event in 
D2409 
True proportion 
Sample size 
Probability of seeing at least 
one event 
0.001 
40 
0.039 
0.003 
40 
0.113 
0.005 
40 
0.182 
0.007 
40 
0.245 
0.01 
40 
0.331 
0.025 
40 
0.637 
0.05 
40 
0.871 
0.1 
40 
0.985 


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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 CFR 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of 
Helsinki. 
10.2 
Informed consent procedures  
Eligible patients 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(s) of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents.  
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval. 
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus. 
10.3 
Responsibilities of the investigator and IRB/IEC  
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made. 


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10.4 
Publication of study protocol and results  
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
11 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. All significant protocol deviations will be recorded and reported in the CSR. 
11.1 
Protocol Amendments  
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring should be followed. 
12 
References 
Goodin DS, Frohman EM, Garmany GP, et al (2002). Disease modifying therapies in multiple 
sclerosis: Subcommittee of the American Academy of Neurology and the MS Council for 
Clinical Practice Guidelines. Neurology; 58: 169-78 
Polman CH, O'Connor PW, Havrdova E, et al (2006). A randomized, placebo-controlled trial 
of natalizumab for relapsing multiple sclerosis. N Engl J Med; 354(9): 899-910. 
Ransohoff RM (2007). Natalizumab for Multiple Sclerosis. N Engl J Med; 356: 2622-2629. 
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika, 26; 404–413. 
 

SAP_001.pdf: 
 
Official Title: 
Long-term, open-label, multicenter study assessing long-term 
cardiovascular risks in patients treated with fingolimod 
NCT Number: 
NCT02232061 
 
Document Date: 
 
SAP Version 2: 21 August 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Development
FTY720D (Fingolimod)
CFTY720D2403 & CFTY720D2406 & CFTY720D2409
Long-term, prospective, multinational, parallel-cohort study 
monitoring safety in patients with MS newly started with fingolimod 
once daily or treated with another approved disease-modifying 
therapy
Long-term, prospective, non-interventional, multinational, parallel-
cohort study monitoring safety in patients with MS recently initiated 
with fingolimod once daily or treated with another approved 
disease-modifying therapy
Long-term, open-label, multicenter study assessing long-term 
cardiovascular risks in patients treated with fingolimod
RAP Module 3 – Detailed Statistical Methodology
Author(s):
 (CRO Trial Statistician), 
 
(CRO Statistician), 
(Novartis Trial 
Statistician)
Document type:
RAP Documentation for final analyses
Document status:
Final 2.0, Amendment 1
Release date:
21-Aug-2020
Number of pages:
63
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History 
Version
Date
Changes
Draft 1.0
16-Aug-2019
First draft.
Draft 1.1
6-Dec-2019
Implementation of comments on draft 1.0 and decisions made during RAP 
discussion TCs.
Final 2.0
18-Mar-2020
Finalization of document. Few additional changes based on comments and 
input from programming. Additional analysis for incidence rate differences.
Additional serious cardiovascular event table comparing pooled cardiac set 
to Other DMT patients stratified by Framingham risk score category.
Final 2.0 
Amendment 1
21-Aug-2020
Implementation of dry-run 2 comments from Novartis:

Adjustment of the use of data cutoff date in programming changed 
due to missing study completion visits in several patients

Clarification of adverse event classification by time interval

Analyses of AEs excluding certain time intervals added back into 
RAP (erroneously deleted from previous versions)

Incidence rate ratios added for AE analyses by subgroups

Various outputs for substudy analyses of D2403 added

Notable criteria for liver function tests corrected

List of cardiovascular risk factor preferred terms extended


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................5
2
PASSAGE reports and use of the virtual data warehouse...................................................6
3
Pooling of data from patients who discontinue D2406 to enter D2409 ..............................6
4
Statistical and analytical plans.............................................................................................7
4.1
Terminology – MS DMT, permanent switch, initial cohort treatment, first 
DMT corresponding to cohort assignment ..............................................................7
4.2
General reporting approaches..................................................................................8
4.3
Definitions ...............................................................................................................9
4.3.1
Cut-off date .............................................................................................9
4.3.2
Day 1 and other time definitions.............................................................9
4.3.3
Time at risk .............................................................................................9
4.3.4
Definition of ‘baseline’ .........................................................................10
4.3.5
Duration derivation ...............................................................................10
4.4
General rules..........................................................................................................11
4.4.1
General rules on statistics to present.....................................................11
4.4.2
General rules for tables and listings......................................................11
4.4.3
Partial dates (imputation rules) .............................................................11
4.5
Analysis sets ..........................................................................................................12
4.5.1
Definition of subgroups/stratifications for analysis ..............................13
4.6
Characteristics of participants................................................................................14
4.6.1
Disposition ............................................................................................14
4.6.2
Protocol deviations................................................................................15
4.6.3
Cause of death from study completion form.........................................15
4.6.4
Demographic variables..........................................................................15
4.6.5
MS baseline characteristics and MS disease history variables .............16
4.6.6
Prior MS DMT......................................................................................17
4.6.7
Medical history......................................................................................18
4.7
Study medication duration of exposure.................................................................19
4.8
Time at risk............................................................................................................19
4.9
Reasons for switch from treatment........................................................................19
4.10
Switches from first DMT corresponding to cohort assignment and initial 
cohort treatment, and specified DMTs taken as the initial cohort treatment.........20
4.11
Concomitant medications ......................................................................................20
4.12
Effectiveness evaluation........................................................................................21


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4.12.1
General effectiveness rules ...................................................................21
4.12.2
Relapses.................................................................................................21
4.12.2.1
Annualized relapse rate (ARR).............................................................21
4.12.2.2
MS relapse characteristics.....................................................................22
4.12.3
EDSS.....................................................................................................22
4.13
Safety evaluation ...................................................................................................23
4.13.1
General safety rules...............................................................................23
4.13.2
Adverse events ......................................................................................23
4.13.3
Laboratory data .....................................................................................28
4.13.3.1
Abnormal liver function tests................................................................28
4.13.3.2
Clinically notable laboratory abnormalities..........................................29
4.13.3.3
Other laboratory data.............................................................................29
4.13.4
Routine vital signs.................................................................................29
4.13.5
First dose monitoring (Group F only)...................................................29
4.13.5.1
First dose monitoring of vital signs.......................................................30
4.13.5.2
First dose monitoring procedures..........................................................30
4.13.6
Ophthalmic and dermatological examination .......................................32
4.14
Other assessments..................................................................................................32
4.14.1
D2403 Patient Reported Outcomes.......................................................32
4.14.2
D2403 sub-studies.................................................................................36
4.14.3
Pool of D2409 and D2403 cardiac sub-study data................................38
4.14.4
D2409 study ..........................................................................................39
4.15
Visit windows........................................................................................................40
5
General statistical methodology ........................................................................................41
6
Reference list.....................................................................................................................44
Appendix A
General principle on analysis sets and data selection in the virtual 
data warehouse
46
Appendix B
Illustration of VDW key dates ..............................................................48
Appendix C
Sample Illustration of Prior MS DMT and Initial cohort treatment 
ongoing at study entry duration calculations.....................................................................49
Appendix D
Criteria for notable laboratory abnormalities........................................50
Appendix E
Notable vital signs criteria ....................................................................51
Appendix F
Mapping of MS medications to the 7 categories of 1st DMT 
corresponding to cohort assignment..................................................................................52
Appendix G
Framingham risk score calculation .......................................................53
Appendix H
Concomitant medications treating sBP .................................................56
Appendix I
Cardiovascular risk factors...................................................................57
Appendix J
Risk charts for European CVD risk score.............................................61


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Appendix K
Serious cardiovascular event definition ................................................63
1
Introduction
This analysis plan provides a description of the analyses needed for studies CFTY720D2403, 
CFTY720D2406, CFTY720D2409 and for a combined analysis of all three studies (in the 
following referred to as pooled analysis) as well as substudy analyses, where applicable, for 
the final analyses reporting. Data will be analyzed by 
, Germany
according to the data analysis section of the study protocols (Section 9 of CFTY720D2403, 
Section 7 of CFTY720D2406 and Section 9 of CFTY720D2409) which are available in 
Appendix 16.1.1 of the respective CSRs. Important information is given in the following 
sections and details are provided, as applicable, in Appendix 16.1.9 of the CSRs.
CFTY720D2403 (Study protocol Version 02):
CFTY720D2403, in the following referred to as D2403, is a multinational, long-term, 
prospective, parallel-cohort study to monitor and further describe the long-term safety of 
fingolimod (FTY720). It includes patients with relapsing forms of multiple sclerosis (MS) that 
have been newly prescribed FTY720 by their treating physician or patients that are treated
within six months prior to study entry with other disease-modifying therapies as part of their 
MS treatment in accordance with the respective local prescribing information and routine 
clinical practice.
During the course of the study, patients will be allowed to switch MS DMT (i.e. FTY720 or 
other DMT) while remaining in the study except those switching to cytotoxic agents (e.g. 
mitoxantrone), natalizumab or an investigational DMT, in which case they are to discontinue 
from the study.
CFTY720D2406 (Study protocol Version 03):
CFTY720D2406, in the following referred to as D2406, is a multi-country, multi-center, long-
term, prospective, non-interventional, parallel cohort study to monitor and further describe the 
long-term safety of FTY720. It includes patients with relapsing MS who either have been 
recently initiated with FTY720 by their treating physician or who are treated within six 
months prior to study entry or starting with other DMT as part of their MS treatment in 
accordance with the respective local prescribing information and routine clinical practice.
During the course of the study, patients will be allowed to switch MS DMT (i.e. FTY720 or 
other DMT) while remaining in the study unless they are converted to an investigational DMT.
CFTY720D2403 and CFTY720D2406 are similar studies and together called the PASSAGE 
study.
CFTY720D2409 (Study protocol Version 01):
CFTY720D2409, in the following referred to as D2409, is a multi-country, multi-center, long-
term, prospective, interventional, study to estimate the long-term cardiovascular risk of 
fingolimod in patients who experienced a cardiovascular event during the first 24 hours of 
fingolimod treatment initiation or re-initiation in study D2406 which led to overnight 
monitoring or met seriousness criteria. Patients eligible and consenting to participation in 


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study D2409 will discontinue their study D2406 participation and be followed in study D2409. 
Study D2409 enrollment period will be open until 1-year before the end of study D2406 and 
the study will last until the end of study D2406 i.e. five years after the last patient has been 
enrolled in Study D2406. Within the summaries, patients will be reported under their original 
patient number from study D2406 and not be considered separate patients.
2
PASSAGE reports and use of the virtual data warehouse
The virtual data warehouse (VDW) is a collection of pooled datasets containing most of the 
FTY720 data in the MS indication. The VDW uses harmonized rules across all FTY720 trials. 
For now it is updated every 12 months (every 6 months until February 2017), with the main 
goal of preparing a periodic safety update report (PSUR) deliverable on a yearly basis. It does 
not pre-specify all possible analyses, but it contains rules and datasets to facilitate future
analyses. 
For reporting of PASSAGE studies, it has been decided to align the analysis concept with 
other Gilenya analyses, that is, to align it with the VDW (and thus the PSUR). PASSAGE 
analyses will be done as follows:

Wherever possible, PASSAGE analyses will use the VDW analyses datasets, but filter on 
the appropriate studies (that is, D2403, D2406, D2409 or D2403/D2406/D2409). In that 
case, the VDW datasets (programmed by Novartis) will be made available to 
, 
who will program the analysis outputs.

For specific data analyses where data are not analysis-ready in the VDW, the 
programming of the derived datasets as well as the programming of the analysis outputs 
will be performed by 
. For these analyses too, the approach used will be 
consistent with the general approach used in the VDW, where applicable. 
This document will clarify for each analysis whether VDW analysis datasets will be used, or 
whether there will be a need to derive the analysis datasets.
3
Pooling of data from patients who discontinue D2406 to 
enter D2409
Data for patients who discontinue study D2406 to enter D2409 will be appended for the 
pooled PASSAGE analysis, i.e., they will be reported under the identification number a 
patient was assigned to at the beginning of D2406 and will be analyzed as if collected under a 
single study. That means, e.g., adverse events for these patients will be reported for the entire 
duration of study participation within both studies and the reporting period will be the entire 
time from the first dose within D2406 until the end of D2409. Baseline data, demographic 
characteristics, medical history, disease characteristics and previous MS treatment etc. will be 
taken from the D2406 study. The study completion status, however, will be taken from D2409.
Where specific rules for data pooling are needed for analysis these will be stated in the 
respective sections of this document.


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4
Statistical and analytical plans
4.1
Terminology – MS DMT, permanent switch, initial cohort 
treatment, first DMT corresponding to cohort assignment
MS DMT is used to designate all MS disease modifying therapies: FTY720 and/or any other 
MS DMT. 
A permanent switch is defined as a switch from FTY720 to non-FTY720 MS DMT, or a 
switch from a non-FTY720 MS DMT to FTY720.
Initial cohort treatment is used to designate:

For patients assigned to the FTY720 cohort, the first sequence of FTY720 treatment 
(interruptions in FTY720 treatment are allowed) taken in the study, before first permanent 
switch to a non-FTY720 DMT.

For patients assigned to the other DMT cohort, the first sequence of all non-FTY720 MS 
DMTs (not differentiating between the different non-FTY720 MS DMTs, interruptions are 
allowed) taken in the study, before first permanent switch to FTY720. 
Note: the initial cohort treatment is either ‘FTY720’ or ‘other DMT’. To present initial 
cohort treatment data, VDW variable TRTN_CO will be used.
First DMT corresponding to cohort assignment is used to designate:

For patients assigned to the FTY720 cohort, the first FTY720 treatment taken during the 
study, prior to any switch in DMT occurring after the initial cohort treatment date and 
prior to any interruption in FTY720 of more than 45 days.  

For patients assigned to the other DMT cohort, the first non-FTY720 DMT taken during 
the study, prior to any switch in DMT occurring after the initial cohort treatment date and 
prior to any interruption in first DMT of more than 45 days. This will be one single drug. 
Note: The first DMT corresponding to cohort assignment will be classified under 
7 categories, based on the preferred term: FTY720, Interferon, Glatiramer Acetate, 
Dimethyl Fumarate, Teriflunomide, Natalizumab and other MS therapies. To present data 
by first DMT corresponding to cohort assignment, (i.e. by the 7 above categories), VDW 
variable TRTN_RI should be used. Mapping of medication preferred terms to these 
7 categories is available in Appendix F.
For a patient with a permanent switch, first dose of treatment at permanent switch will be 
defined as follows:

For patients assigned to the FTY720 cohort, it will be the first dose of non-FTY720 MS 
DMT taken during the study (after the first dose of FTY720 taken during the study)

For patients assigned to the other DMT cohort, it will be the first dose of FTY720 taken 
during the study (after the first dose of non-FTY720 DMT taken during the study)
Link to VDW: the date of first dose of treatment at first permanent switch is available in 
FIRSMD9O.


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Example
Patient 1 was assigned to the FTY720 cohort. He started FTY720 on the 3rd day in the study 
and switched to Avonex after 1.5 years. Patient 2 started Avonex 3 months prior to study 
entry, then switched to Glatiramer acetate after 1 year, and finally switched to FTY720 after 4 
years. 
For patient 1, both the initial cohort treatment and the first DMT corresponding to cohort 
assignment will be designated as FTY720. The first dose of treatment at permanent switch 
will be the first dose of Avonex.
For patient 2, while the initial cohort treatment will consist of Avonex followed by
Glatiramer acetate the first DMT corresponding to cohort assignment will be Avonex alone. 
The first dose of treatment at permanent switch will be the first dose of FTY720.
4.2
General reporting approaches
One of the key features of the PASSAGE studies is that patients are allowed to switch DMT, 
while remaining in their original cohort (for example, a patient enrolled in the ‘Other DMT’ 
cohort can later decide to switch to FTY720). With this specific feature in mind, it has been 
decided to look at the PASSAGE data using different approaches are used:
1. “All patients, by initial cohort treatment” (Group G) – providing rigorous data 
allowing meaningful comparisons: Where all patients will contribute to the analyses and 
they will be grouped by original cohort assignment (i.e. the cohort they were assigned to at 
study entry). Unless otherwise specified, safety analyses in Group G will include data 
from first dose date in study of initial cohort treatment to the last dose date of initial cohort 
treatment + 45 days, day before the first dose date of the first permanent switch, or cut-off 
date, whichever is earliest. Unless otherwise specified, effectiveness analyses in Group G 
will only use data collected on the first DMT corresponding to cohort assignment (i.e. data 
from one single drug). 
Link to VDW: this approach corresponds to the Group G cohort approach.
2. “All FTY720 treated patients” (Group F) - comprehensive view on long-term 
FTY720 data: all patients who took at least one dose of FTY720 in the study will be 
included in the analyses. Unless otherwise specified, all data collected from first dose of 
FTY720 until the last dose of FTY720 +45 days or cut-off date, whichever is earlier will 
be considered, regardless of switch to other DMT. No analyses of effectiveness are 
planned for Group F.
Link to VDW: this approach corresponds to the VDW Group F approach.
In this document and in statistical outputs, the wordings Group G and Group F will be used to 
refer to these two ways of looking at the data.
As a general rule, Group G outputs will be generated for each individual study (D2403 and 
D2406) as well as for the pooled D2403/2406 report. Group F analyses will be generated for 
the pooled analysis and each individual study.


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4.3
Definitions
4.3.1
Cut-off date
The cut-off date will be set to the DB lock date for the individual studies in the VDW. If the 
DB lock dates differ the cut-off date will be set to the latest DB lock date.
4.3.2
Day 1 and other time definitions
An illustration of the key dates available in the VDW is provided in Appendix B.
Day 1 is defined as:

In group G, Day 1 is the day of the first administration of initial cohort treatment in the 
study (VDW variable: Group G Day 1 is the day of FIRSMD1O).

In group F, Day 1 is the day of the first administration of FTY720 in the study (VDW
variable: Group F Day 1 is the day of FIRSMD3O).
Note: Day 1 may be different from the baseline visit (Visit 1) day.
Date of last dose of initial cohort treatment (used in Group G safety analyses) is defined as 
the date of last dose of initial cohort treatment, prior to first permanent switch (see Section 4.1 
for definitions). If the last dose date of initial cohort treatment is missing it will be imputed 
using the end of study participation date or the last visit date if the former is not available.
(VDW variable: LSTSMD8O).
Date of last dose of FTY720 (used in Group F analyses) is defined as the date of last dose of 
FTY720 taken during the study. In the case where a patient took FTY720, then switched to 
another DMT then came back to FTY720, the date of the very last dose of FTY720 will be 
used (VDW variable: LSTSMD3O). If the dose date of FTY720 is missing it will be imputed 
using the end of study participation date or the last visit date if the former is not available.
Date of last dose of first DMT corresponding to cohort assignment (used in Group G 
effectiveness analyses) is defined as the date of last dose of first DMT corresponding to 
cohort assignment (as defined in Section 4.1) prior to any switch in DMT and prior to an 
interruption of more than 45 days. If the date of last dose of first DMT is missing it will be 
imputed using the end of study participation date or the last visit date if the former is not 
available. (
 variable: LSTDMT1).
4.3.3
Time at risk
The time at risk matches the time generally considered in safety summaries. The time at risk 
will be used in the analysis of adverse events to derive the (exposure-adjusted) incidence rates 
and is defined as follows:

In Group G, summaries by first DMT corresponding to cohort assignment: time at risk 
(days) is the number of days from first dose date of first DMT corresponding to cohort 
assignment (i.e. Day 1) to last dose date of first DMT corresponding to cohort assignment 
prior to any switch in DMT and prior to any interruption in the first DMT corresponding 
to cohort assignment of more than 45 days + 45 days. If this date lies after the cut-off date, 
the cut-off date will be used instead (Based on 
 derived variable TMATRSK2).


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
In Group G, all other AE summaries: time at risk (days) is the number of days from first 
dose date of initial cohort treatment in the study (i.e. Day 1) up to the last dose date of 
initial cohort treatment + 45 days, day before first dose date of treatment after permanent 
switch, or cut-off date whichever is earliest.  (Link to VDW: this will be derived as 
(CUTO_CO – FIRSMD1O +1)).

In Group F: time at risk (days)  is the number of days from first dose date of FTY720 in 
the study up to last dose date of FTY720 +45 days or cut-off date, whichever is earlier. 
(VDW variable: TMATRSK)
4.3.4
Definition of ‘baseline’
In these observational studies, where patients were allowed to enter when already receiving 
study treatment (for details please refer to the study protocols), there is no classical definition 
of "baseline value". The following values will be used in the analyses :

In group G, the value prior to first dose of initial cohort treatment in study refers to the 
last measurement prior to administration of the first dose of initial cohort treatment in the 
study. If there is no such measurement, the measurement taken on the day of 
administration of the first dose of initial cohort treatment in the study will be used. For 
patients who never received a dose of initial cohort treatment, data up to and including 
Visit 1 may be used.

In group F, the value prior to first dose of FTY720 in study refers to the last measurement 
prior to the administration of the first dose of FTY720 in the study. If there is no such 
measurement, the measurement taken on the day of administration of the first dose of 
FTY720 in the study will be used if available.
Note about vital sign first dose monitoring assessments: on the day of first intake of FTY720, 
a pre-dose measurement and post dose measurements will be taken. Only the pre-dose 
measurement will be considered for the value prior to first dose of initial cohort or FTY720 in 
the study, if available.  
4.3.5
Duration derivation
Unless otherwise specified for a specific panel or variable, duration variables will be derived 
according to the following rules:

Duration (in days) = [End date – start date +1]

Duration (in weeks) = [End date – start date +1]/ 7 

Duration (in months)= [End date – start date +1]/30  

Duration (in years) = [End date – start date +1]/365.25  
Duration variables which are to be expressed in units greater than day (e.g. the duration of MS 
since first symptoms in years) will be rounded to 1 decimal place.


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4.4
General rules
4.4.1
General rules on statistics to present
Categorical data will be presented as absolute and relative frequencies. Percentages will be 
rounded to 1 decimal place. For frequencies of categorical variables, a category of ‘Missing’ 
will be added if at least one patient has no response.
Summary statistics for continuous variables will include n, percentage of patients out of 
analysis set, mean, standard deviation, minimum, lower quartile (25th percentile), median, 
upper quartile (75th percentile), and maximum. The mean, median and percentiles will be 
rounded to 1 additional decimal place compared to the original data. Standard deviation will 
be rounded to 2 additional decimal places. Minimum and maximum will be displayed with the 
same accuracy as in the original data. 
4.4.2
General rules for tables and listings
Unless otherwise stated, summary tables and listings will include all patients in their 
respective analysis sets. For more details on the analyses set and data considered in specific 
analyses, please refer to specific sections in this document.
Except for the listings presenting data related to participant’s characteristics and unless 
otherwise stated, the following rules will apply to listings:
Group G listings
Group G listings will include all data collected in the study in the corresponding panel (even if 
collected prior to Group G Day 1).
Group F listings
Unless otherwise specified, Group F listings will include all data collected on or after first 
dose of FTY720 in the study in the corresponding panel.
Combined listings
The majority of the listings will include patients belonging to Group G and/or Group F, and 
will include all data mentioned in the above descriptions for Group G and Group F listings.
Flags to identify the groups will be added, as necessary.
4.4.3
Partial dates (imputation rules)
Specific imputation rules may apply to certain panels (e.g. concomitant medications) and are 
described in the relevant sections. If no imputation rules are described then the general 
imputation rules apply to partially missing or impossible dates

If the year is missing or impossible (e.g. 12-Jan-1911), then the date will be imputed as 
missing.

If the year is not missing and possible, but the month is impossible (i.e. the 3 digits for 
month within the character date variable contain characters not belonging to a valid month 


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abbreviation) or missing (e.g. 17-XXX-2010), then the year-information will be kept and 
July 1st will be imputed (1-July-2010).

If the year and the month are not missing and possible, but the day is impossible or 
missing (e.g. XX-FEB-2009), then the year and month will be kept, the 15th will be 
imputed (15-FEB-2009).
In the listing, when date variables from VDW are presented, the values in VDW data set will 
be presented. If VDW variables are not available and data from raw data set should be used, 
the original data without imputation will be presented.
4.5
Analysis sets 
An analysis set is defined as a subset of patients who share common criteria. The analysis sets 
used in each of the 2 groups are defined below:
Group G - “all patients” 

Enrolled set: All patients who were enrolled into a study and were categorized to a cohort 
at the start of the study, excluding patients with a protocol deviation severity code of 8 
(8=exclude from all analyses). (VDW variable: ENR)

Safety set: All enrolled patients who received at least one dose of treatment corresponding 
to the cohort they were assigned to, excluding patients with a protocol deviation severity 
code of 5 (5=exclude from all safety analyses) or 8 (8=exclude from all analyses). (VDW
variable: SAF_G)

Effectiveness set: All patients who were treated with the first DMT corresponding to 
cohort assignment for a minimum of 180 days in the study, excluding interruptions. The 
determination of whether a patient completed a minimum of 180 days is based on the 
duration on first DMT, which is the time in study from first dose date of first DMT 
corresponding to cohort assignment to last dose date of first DMT corresponding to cohort 
assignment prior to any switch in DMT and prior to any interruption in the first DMT 
corresponding to cohort assignment of more than 45 days, excluding any interruptions. 
Patients with a protocol deviation severity of 0 (0=exclude from all efficacy analyses), 1 
(1=exclude from all per protocol analyses), or 8 (8=exclude from all analyses) will be 
excluded (
-derived variable: EFF_G.)

 
In Group G analyses on the enrolled set and on the safety set, patients will be grouped 
according to the cohort they were assigned to at study entry (VDW variable: TRTN_CO). 
In Group G analyses on the effectiveness set, patients will be grouped according to the first 
DMT corresponding to cohort assignment. Specifically, the following DMTs will be 
presented: FTY720, Interferon, Glatiramer Acetate, Dimethyl Fumarate, Teriflunomide, 
Natalizumab, and other MS therapies (VDW variable: TRTN_RI).  
Group F - “all FTY720 treated patients”

Safety set: All enrolled patients who received at least one FTY720 dose in the study. 
(VDW variable: SAF_EF)


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In Group F, there will be one single group, the FTY720 group. 
Disposition, demographics, baseline characteristics, and medical history will use the enrolled 
set for Group G and safety set for Group F. Safety analyses (adverse events, vital signs, 
laboratory data, FTY720 first dose administration monitoring on ECG and vital signs) will be 
performed using the safety sets. Effectiveness analyses will be based on the effectiveness set.
The number and percentage of patients in each analysis set will be summarized for Group G. 
The enrolled population will be used as the denominator for percentages. The number of 
patients in the safety set will be summarized for Group F. Group F patients will be divided 
into patients who started in FTY720 cohort and patients who switched to FTY720. A listing 
will also be presented for the analysis sets.
4.5.1
Definition of subgroups/stratifications for analysis
Certain analyses, as specified in the corresponding sections of this document, will be 
performed on the following subgroups of patients:

Patients naïve to any prior MS DMT: This subgroup will be defined as patients who do 
not have any prior DMTs (Day 1). It should be noted that prior DMTs in this definition
include initial cohort treatments already ongoing at study start. Note: for some analyses in 
that subgroup, both cohorts will be presented, while for some other only the FTY720 
cohort will be used.

Patients previously treated with any MS DMT: This subgroup will be defined as all 
patients who have a history of any MS DMT (including FTY720) prior to study start (Day 
1).

Patients never treated with FTY720. This subgroup will be defined as patients who 
were never treated with FTY720 prior to study start (Day 1).

Patients in the FTY720 cohort split by subgroups based on the type of MS therapy 
previously used: The last MS-DMT before switching to initial cohort treatment, as 
defined in Section 4.6.5., will be used to defined these subgroups. MS DMTs to be 
considered will be the following: interferon beta-1a, interferon beta-1b, glatiramer acetate, 
natalizumab, dimethyl fumarate and teriflunomide.

Patients who started their initial cohort treatment within the study.

Patients who had an AE categorized as cancer: This subgroup will be defined as all 
patients that have at least one adverse event categorized as cancer. The corresponding AEs 
are identified as all malignant forms of cancer in the system organ class "Neoplasms 
benign, malignant and unspecified (incl cysts and polyps)".

Patients stratified by duration of previous MS DMTs: Patients will be split into 
subgroups according to duration of previous MS DMTs <= 3 years and > 3 years.

Patients stratified by age group: Patients will be split into subgroups according to  age 
(at first dose of initial cohort treatment) <= 40 years and > 40 years.

Patients stratified by gender: Patients will be split into subgroups according to gender.

Patients stratified by ethnicity: Patients will be split into subgroups according to 
ethnicity.


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
Patients stratified by geographic region: For D2403 use North America, South America
and APAC. For D2406 use Europe and APAC. For pooled analysis use North America,
South America, Europe and APAC.

Patients stratified by Framingham risk score category: Only done for pooled cardiac 
analysis. Patients will be split into subgroups according to the median Framingham risk 
score calculated over all patients in the pooled cardiac set who had FTY as initial cohort 
treatment.
The following table shows an overview of the usage of subgroups in the respective analyses:
Subgroup definition
D2403
D2406
Pooled
General subgroups
Patients naïve to any prior MS DMT
X
X
X
Patients previously treated with any MS DMT
X
X
X
Patients who were never treated with FTY720
X
X
X
Patients in the FTY720 cohort split by subgroups based on 
the type of MS therapy previously used
X
X
X
Patients who started their initial cohort treatment within the 
study
X
X
X
Patients who had an AE categorized as cancer
X
X
X
Subgroups specific for AE analysis
Patients stratified by duration of previous MS DMTs
X
X
X
Patients stratified by age group 
X
X
X
Patients stratified by gender
X
X
X
Patients stratified by ethnicity
X
X
X
Patients stratified by geographic region
X
X
X
Patients stratified by Framingham risk score category*
* Will only be done for pooled cardiac analysis.
4.6
Characteristics of participants
4.6.1
Disposition
The number and percentage of patients who completed the study or discontinued the study 
prematurely along with the primary reason for discontinuation will be presented for Groups F 
and G.
For patients who discontinue from study D2406 and who continue in study D2409 the 
completion status from D2409 will be used in the pooled tables.
Patient disposition will also be provided for the following subgroups defined in Section 4.5.1
above:

Patients naïve to any other DMT

Patients previously treated with any MS DMT


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
Patients never treated with FTY720.

Patients who had an AE categorized as cancer 
4.6.2
Protocol deviations
The number and percentage of patients with protocol deviations will be summarized for 
Group G. This will be done for individual studies and pooled analysis.
4.6.3
Cause of death from study completion form
4.6.4
The principal cause of death from the study completion page will be 
summarized by primary system organ class, preferred term for Group 
G, Enrolled set and Group F, safety set.Demographic variables
Demographic characteristics include age (derived), gender, race, and ethnicity collected on the 
demography CRF, height, and body weight recorded on the vital signs CRF, and the body 
mass index (BMI) calculated as (body weight in kilograms) / (height in meters)2.
In Group G, age will be calculated at first dosing date of initial cohort treatment (VDW
variable FIRSMD1O) and height and body weight values prior to first dose of initial cohort 
treatment in the study will be presented. If first dosing date is missing, then the Visit 1 date 
will be used for calculation. In Group F, age will be calculated at first dose of FTY720 during 
the study and height and body weight values prior to first dose of FTY720 during the study
will be presented. See Section 4.3.4 for more details on derivation of baseline measurement.
Weight that is collected in pounds will be converted to kilograms using 1 kg=2.2 lb. Height 
that is collected in inches will be converted to cm using 1 in=2.54 cm.
For other variables, data as collected on the demography CRF will be presented.
The number of patients with any smoking history (i.e. who answered 'yes' to the question 'Has 
patient any smoking history?”) and those who smoke at study entry will be presented for 
Group G. Alcohol history at study entry will be summarized by category (abstinent, less than 
1 drink per day, 1-2 drinks per day, 3 or more drinks per day, unknown) for Group G.
The number of patients per geographic region and country will also be presented for Group G.
All demographic and baseline characteristic data described in this section will be summarized 
by presenting frequency and percentage (for categorical variables) and summary statistics (for 
continuous variables). Age group will also be summarized for the categories of <18, 18-40, 
41-64, >=65 years of age.
Demographic characteristics will also be provided for the following subgroups defined in 
Section 4.5.1 above:

Patients naïve to any other DMT

Patients previously treated with any MS DMT

Patients never treated with FTY720

Patients who started their initial cohort treatment within the study.

Patients who had an AE categorized as cancer


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4.6.5
MS baseline characteristics and MS disease history variables
MS disease history and EDSS at study entry (Group G) and prior to first dose of FTY720 
during the study (Group F) will be summarized.
Details of MS diagnosis (RRMS, SPMS, PPMS, other) will be summarized with the number 
and percentage of patients for Group G and Group F. Duration of MS since diagnosis and 
duration of MS since first symptom will be summarized as a continuous variable and as a 
categorical variable using the following categories: 0-<1, 1-<2, 2-<5, 5-<10, 10-<15, >=15 
years. Number of relapses in the 12 months prior to study entry and between 12 and 24 
months prior to study entry will be summarized as a continuous variable and as a categorical 
variable using the following categories: 0, 1, 2-3, 4-5, >5. The total number of relapses in the 
12 months prior to study entry will be presented. The number and percentage of relapses that 
required steroid treatment will be presented. Time since the onset of the most recent relapse at 
study entry (months) will be derived for each patient using (date of Day 1 – the most recent 
relapse onset date + 1)/30. 
The most recent EDSS score available at baseline will be summarized as a continuous 
variable. The subset of most recent EDSS scores that were not assessed in the course of a 
relapse will also be summarized.
For Group G, duration variables (duration of MS since diagnosis, duration of MS since first 
symptom, time since onset of the most recent relapse) will be calculated based on Group G 
Day 1 date (i.e. the date of first dose of initial cohort treatment taken during the study) and 
data collected on the MS history CRF page will be presented.
For Group F, duration will be calculated based on Group F Day 1 date (i.e. the date of first 
dose of FTY720 taken during the study). In this group, since a patient may start FTY720 at 
any time during the study (e.g. after switching from another MS DMT), any MS disease status 
(relapses and EDSS) collected prior to the first dose of FTY720 in the study will be 
considered an MS disease history. The EDSS data from both the MS history CRF page and 
the MS status page will be presented to represent Group F MS disease history. Only the 
number of relapses in the last 12 months and between the last 12 and 24 months before study 
entry as collected in the MS history CRF will be summarized for patients in Group F.
The patients’ status of previous exposure to varicella zoster virus (VZV) combined with 
whether or not patient had VZV serology test prior to FTY720 initiation will be summarized 
by frequency for Group F using the safety set.
MS baseline characteristics and disease history variables will also be provided for the 
following subgroups defined in Section 4.5.1 above:

Patients naïve to any other DMT

Patients previously treated with any MS DMT

Patients never treated with FTY720

Patients who started their initial cohort treatment within the study

Patients who had an AE categorized as cancer.


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4.6.6
Prior MS DMT
To facilitate data summarization, the prior MS DMTs will be categorized into Fingolimod, 
Interferon, Glatiramer Acetate, Dimethyl Fumarate, Teriflunomide and Natalizumab, as 
defined in Appendix F. All other MS DMT will be summarized as recorded by the preferred 
term. 
For Group G, MS DMTs that were taken prior to Group G - Day 1 will be classified into 
either one of the following mutually exclusive categories, and will be summarized by 
categorized preferred term:

‘Prior MS DMT’: defined as MS DMT that started and ended before initial cohort 
treatment, or 

‘Initial cohort treatment ongoing at study entry’: defined as the initial cohort treatment 
that started before and was continuing at the study entry.
The number and percentage of patients for each prior MS DMT as well as each initial cohort 
treatment ongoing at study entry will be summarized.
The ‘last MS DMT before switching to initial cohort treatment’ defined as the latest MS DMT 
that was taken before starting the initial cohort treatment, will also be summarized by 
categorized preferred term. Duration of exposure to prior MS DMTs, as well as duration of 
exposure to initial cohort treatment ongoing at study start will be summarized descriptively. A 
sample illustration for the calculation of durations for ‘Prior MS DMT’ and ‘Initial cohort 
treatment ongoing at study entry’ is provided in Appendix C. 
Note: Duration of exposure to initial cohort treatment ongoing at study entry will be derived 
as [Study entry date (i.e. Visit 1 date) – first dose of initial cohort treatment prior to study 
entry]. These duration variables are not included in the VDW and will be derived for 
PASSAGE. The patient-years, defined as the sum of the number of days on initial cohort 
treatment ongoing at study entry for all patients in the cohort/365.25, will also be presented.
For Group G summaries, medications from both the Previous MS treatment CRF and the MS 
disease modifying therapy record CRF for D2403 and from the MS disease modifying therapy 
record CRF page for D2406 will be used.
For Group F, all MS DMT with a start date and end date prior to the first dose of FTY720 in 
the study will be considered as prior MS DMT and will be summarized by categorized 
preferred term. The ‘last MS DMT before switching to FTY720’ defined as the latest MS DMT 
that was taken before the first FTY720 dose, will also be summarized by categorized 
preferred term. Duration of exposure to prior MS DMTs will be summarized descriptively. 
This duration variable will be derived for PASSAGE (not available in VDW).
For Group F summaries, medications from both the Previous MS treatment CRF and the MS 
disease modifying therapy record CRF for D2403 and from the MS disease modifying therapy 
record CRF for D2406 will be used.
All data will be listed. Note that the first version of the CRF page for D2403 did not collect 
start dates for the MS DMT so that some DMT records may have missing start dates.


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Note about ‘treatment naïve patients’: in the prior MS medication table, all patients for whom
a record of MS medication prior to study entry is available in the database will be presented. 
For the rest of the patients (i.e. the 'treatment naïve patients'), it will mean that no record was 
available in the database. It does not necessarily mean that they were all treatment naïve.
The percentage of patients by cohort treatment (Group G) or study (Group F) will be 
presented as bar chart for number of prior MS DMTs (0, 1, 2, etc.) and for each individual 
prior MS DMT. The duration of prior MS DMT will be presented in a box plot. The bar chart 
and box plot will be displayed in a multi-panel plot. 
The specific imputation rule will be applied on dose start date of MS DMT. 

If start date of MS DMT (STTDOS1D in CRF) is incomplete then 

If only year (yyyy) is available, then imputed date will be 1-Jan-yyyy.

If both year (yyyy) and month (mmm) are available, then impute date will be 01-
mmm-yyyy.
The imputation of dose end date will follow the rule in Section 4.4.3.
4.6.7
Medical history
Relevant medical history and current medical conditions will be summarized as frequency and 
percentage of patients with relevant medical history/condition by primary system organ class 
(SOC) and preferred term using the MedDRA. All coded terms will be included in the 
summary regardless of whether the “Mark if no history” box was selected on the CRF. For 
Group F adverse events that occurred prior to the first dose of FTY720 in the study will be 
treated as medical history.
Data will be summarized by cohort treatment for Group G and for the FTY720 group in 
Group F. Additionally, medical history will also be summarized for Group G restricted to the 
subgroup of patients who had an AE categorized as cancer.
Relevant medical history and current medical conditions
meeting the criteria for 
cardiovascular risk factors will also be summarized with frequency and percentage of patients. 
Additionally selected cardiovascular risk factors will be categorized into four categories 
(Cardiovascular disease, Diabetes mellitus, Hyperlipidaemia and Hypertension) and will be 
summarized by preferred and corresponding category. See Appendix I, Table I-1 for 
definition of cardiovascular risk factors and categorization into categories.
Relevant medical history and current medical conditions as well as only current medical 
conditions will also be provided for the following subgroups:

Patients naïve to any other DMT

Patients previously treated with any MS DMT

Patients never treated with FTY720

Patients who had an AE categorized as cancer.


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4.7
Study medication duration of exposure
Duration of exposure will be presented as a continuous variable and as a categorical variable 
using the categories >=1, >=90, >=180, >=360, >=540, and >=720 etc. days. The patient-
years, defined as the sum of the number of days on specified MS DMT for all patients in the 
cohort/365.25, will also be presented. 
Group G
The following durations of exposure will be summarized for Group G:

Duration of exposure to initial cohort treatment (as defined in Section 4.1) will be 
summarized by initial cohort treatment (FTY720 and other DMT) based on the safety set. 
Duration of exposure will be calculated as the number of days from the first dose of initial 
cohort treatment during the study to the last dose of initial cohort treatment prior to the 
first permanent switch, with all interruptions excluded.. Note: This exposure summary will 
be used to support the safety analyses. (
to derive this exposure variable)

Duration of overall exposure to FTY720 and duration of overall exposure to other DMT
will be summarized based on the safety set and presented by initial cohort treatment. 
Duration of exposure to FTY720 and duration of exposure to other DMT (non-FTY720 
MS DMTs) are defined as the total number of days throughout the entire study that the 
patient took FTY720 or other DMT, respectively, excluding interruptions.  If a patient is 
taking MS DMT on an ongoing basis (no study medication end date in DAR), then the end 
of study participation date or the last visit date if the former is not available will be used in 
place of the last dose date. Note: although this exposure does not support any specific 
analysis, it will provide an overview of the exposure for the whole study.  (Exposure to 
FTY720: 
 derived variable EXPOFTY. Exposure to other MS treatment: 
 derived variable EXPOOTH)
Group F
In Group F, duration of exposure to FTY720 will be summarized based on the safety set and 
presented by study. The duration of exposure will be calculated as the number of days from 
the first dose date of FTY720 during the study to the last dose date of FTY720, with all 
interruptions excluded. Note: This exposure summary will be used to support the safety 
analyses in Group F. (
 derived variable: EXPOFTY.)
4.8
Time at risk
The time at risk, in years, (defined in Section 4.3.3 in days, divided by 365.25 to get time at 
risk in years) will be summarized as a continuous variable by initial cohort treatment for the 
Group G safety set and by study for the Group F safety set. The time at risk, in patient-years 
will also be summarized, and is calculated as the sum of the number of days at risk for all 
patients in the group or cohort, divided by 365.25.
4.9
Reasons for switch from treatment
Reasons for switches from first MS DMT corresponding to cohort assignment (FTY720 in 
FTY720 cohort, corresponding MS DMT in Other DMT cohort), as recorded on the drug 


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administration page, will be summarized. These switches consist of switches from FTY720 to 
non-FTY720 MS DMT as well as switches from first MS DMT corresponding to cohort 
assignment in Other DMT cohort to either FTY720 or another non-FTY720 MS DMT. The 
percentages are based on the total number of patients that had a switch.
Reasons for switch from FTY720 in the study will be summarized for Group F safety set, by 
study. Note that a patient can switch from FTY720 several times throughout the study. 
Therefore, percentages for reasons for switch of FTY720 are based on the total number of 
switches.
4.10
Switches from first DMT corresponding to cohort assignment 
and initial cohort treatment, and specified DMTs taken as the 
initial cohort treatment
The below summaries will be based on the Group G, safety set.
The number and percentage of patients on each first DMT corresponding to cohort assignment
(FTY720, Interferon, Glatiramer Acetate, Dimethyl Fumarate, Teriflunomide, Natalizumab, 
and other MS therapies) will be presented. For each of these possible first DMTs 
corresponding to cohort assignment, the number and percentage of patients who switched 
from first DMT corresponding to cohort assignment and those who did not switch at time of 
database lock will be summarized. For patients in the ‘Other DMT’ initial cohort treatment, 
the number and percentage of patients who switched to FTY720 will also be summarized. All 
percentages will be calculated using the total number of patients in each initial cohort 
treatment as the denominator.
The number and percentage of patients on each MS DMT that was taken as ‘initial cohort 
treatment’, the number and percentage of patients who had a permanent switch, and the 
number of MS DMTs taken as the initial cohort treatment will be summarized by initial 
cohort treatment. Note that for patients in the FTY720 initial cohort treatment, the MS DMT 
taken as initial cohort treatment can only be FTY720, but for patients in the other DMT initial 
cohort treatment, the initial cohort treatment can consist of any MS DMTs prior to the first 
permanent switch and may consist of several non-FTY720 DMTs. 
4.11
Concomitant medications
The number and percentage of patients taking concomitant medications and significant non-
drug therapies will be summarized by preferred term for Group G safety set and for Group F 
safety set. A patient taking the same medication multiple times is counted only once under 
that preferred term. 
For Group G, concomitant medications are medications taken at any time from first dose date 
of initial cohort treatment in the study to last dose date of initial cohort treatment prior to the 
first permanent switch + 45 days. If this date lies after the cut-off date, the cut-off date will be 
used instead. 
For Group F, concomitant medications are medications taken at any time from first dose date 
of FTY720 in study to last dose date of FTY720 + 45 days. If this date lies after the cut-off 
date, the cut-off date will be used instead.


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For imputation of concomitant medication start dates, in cases of missing or partial start dates, 
refer to the VDW Module 8 ‘Concomitant Medication Start Date Imputation (#IMPUTMED)’ 
section.
4.12
Effectiveness evaluation
4.12.1
General effectiveness rules
Unless otherwise specified, all effectiveness analyses will be performed on the effectiveness
set. Effectiveness analyses are not planned for Group F.
For Group G, results will be presented by the first DMT corresponding to cohort assignment. 
Specifically, the following DMTs will be presented: FTY720, Interferon, Glatiramer Acetate, 
Dimethyl Fumarate, Teriflunomide, Natalizumab and other MS therapies (VDW variable: 
TRTN_RI). 
The time on first DMT is defined as the time in study from first dose date of first DMT 
corresponding to cohort assignment to last dose date of first DMT corresponding to cohort 
assignment prior to any switch in DMT and prior to any interruption in the first DMT 
corresponding to cohort assignment of more than 45 days. The time on first DMT will be used 
in the derivation of annualized relapse rate, and it matches the time considered in the 
effectiveness context. (
to calculate a flag for summarizing effectiveness data 
based on 
derived variable LSTDMT1 and VDW variable FIRSMD1O)
4.12.2
Relapses
4.12.2.1 Annualized relapse rate (ARR)
Annualized relapse rate (ARR) is defined as the number of relapses with onset occurring 
during a specific period of time, adjusted to a one-year period. There are two types of ARR 
which will be reported: 

The raw group-level ARR is calculated by taking the total number of relapses with onset 
occurring during a specified time period for all patients in the group, divided by the total 
number of days in the specified time period for all patients in the group, and multiplied by 
365.25. Estimates and 95% confidence intervals for the group-level ARR are derived from 
a negative binomial model with the number of relapses as dependent variable, the first 
DMT corresponding to cohort assignment as explanatory variable and the log of the 
exposure time in years as the time variable. 

The patient-level ARR is calculated for each individual by taking the number of relapses 
with onset occurring during a specified time period for that patient, divided by the total 
number of days in the specified time period for that patient, and multiplied by 365.25.
95% confidence intervals for the patient level ARR are calculated using normal 
approximation. If the lower limit of the CI becomes negative it will be set to 0.
The total number of relapses with onset occurring during the time on first DMT and the total 
time on first DMT (in days) will be reported for all patients in a group, by first DMT 
corresponding to cohort assignment, for the Group G, effectiveness set. Additionally, the 


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group-level ARR and the mean and standard deviation of the patient-level ARR will be 
reported. 
Note that in the MS status CRF page, both the number of relapses since last visit and the 
individual relapses details are collected (start and end dates, recovery status, etc.). In the ARR 
calculation, the relapse start date will be used to derive the number of relapses (and not the 
summary information ‘number of relapses since last visit’). The MS Relapse details CRF page 
will be used in conjunction with the MS status CRF page. When there is no relapse start date 
entered, the number of relapses since the patient’s last visit will be assumed to be 0. 
(Variables needed for the analysis will be derived from the VDW relapse analysis dataset, 
AREL.)
ARR will also be summarized for the FTY720 cohort by the subgroups based on the type of 
MS therapy previously applied as defined in Section 4.5.1 Here, estimates and 95% 
confidence intervals for the group-level ARR are derived from a negative binomial model 
with the number of relapses as dependent variable, and the type of previous MS therapy as 
explanatory variable and the log of the exposure time in years as the time variable.
Further, ARR will be summarized for the subgroup of patients receiving the first dose of their 
initial cohort treatment within this study by first DMT corresponding to cohort assignment, as 
described above.
To account for a potential bias introduced by patients already receiving initial cohort 
treatment prior to entering the study for which exact number of relapses prior to study entry is 
hard to determine, an additional analysis of ARR will be done excluding each patient's first 
180 days following their real first dose of initial cohort treatment. The denominator exposure 
time will be reduced by the same time of interest. It should be noted that a patient may have 
the real first dose of initial cohort treatment before or within this study. If a patient receives 
the real first dose of initial cohort treatment, e.g., 65 days before study start then 115 days 
from the start of study will be removed from these analyses. It should also be noted that 
relapses which occur after the real first dose but prior to the date of informed consent are not 
recorded on the eCRF. Both cohorts are impacted by the eCRF limitation; however, the 
impact of the early cohort start is greater for the other DMTs than for the FTY720 cohort.
4.12.2.2 MS relapse characteristics
The total number of relapses, the number and percentage of patients by recovery status of 
each relapse, whether or not the relapse was treated, and the duration of each relapse (days) 
will be summarized for the Group G, effectiveness set, by first DMT corresponding to cohort 
assignment. Duration of relapse is calculated based on imputed relapse start and end dates to 
restrict relapse duration to up to 90 days.
4.12.3
EDSS
Descriptive statistics on absolute EDSS scores and changes from baseline for Group G will be 
presented. The change from baseline ± SD will be displayed graphically over time by cohort. 
Time intervals are defined by visit windows which are defined in section 4.15.


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4.13
Safety evaluation
4.13.1
General safety rules
Unless otherwise specified, all safety analyses will be performed on the safety set. 
Group G general safety rules – analyses performed according to Group G general safety 
rules will include:

All data from first dose date of initial cohort treatment in the study up to last dose of initial 
cohort treatment + 45 days, day before first dose of treatment at permanent switch, or data 
cut-off date, whichever is earliest.

And SAEs from first dose date of initial cohort treatment in the study up to the day before 
first dose date of treatment at permanent switch, or data cut-off date whichever is earliest. 
Results will be presented by initial cohort treatment (FTY720 and other DMT).
(VDW variable enabling corresponding data selection: FLGSAFCO (data selection flag) or 
CUTO_CO (date))
For results presented by first DMT corresponding to cohort assignment, analyses performed 
will include:

All data from first dose date of first DMT corresponding to cohort assignment in the study 
up to last dose of first DMT corresponding to cohort assignment + 45 days, day before 
switch from first DMT, or cut-off date, whichever is earliest.

And SAEs from first DMT corresponding to cohort assignment in the study up to the day 
before switch from first DMT, or cut-off date, whichever is earliest. 
(Based on 
 derived variable FLGFDMT)
Group F general safety rules – analyses performed according to Group F general safety 
rules will include:

All data from first dose of FTY720 in the study up to last dose date FTY720 + 45 days, or 
cut-off date whichever is earlier.

And all SAEs after first dose of FTY720 in the study (i.e. all SAEs and deaths after the 
first intake of FTY720 in the study will be reported irrespective of when they happened)
And results will be presented for the FTY720 group, by study.
(VDW variable enabling corresponding data selection: FLGSAF_F (data selection flag) or 
CUTO_F (date))
4.13.2
Adverse events
Adverse events will be reported by primary system organ class and preferred term according 
to the Medical Dictionary for Regulatory Activities (MedDRA) . Any other information 
collected (e.g., severity or relation to study drug) will be listed as appropriate. 
Listings of deaths, AEs and SAEs will be provided for Group G and Group F together. Flags 
will show the analyses the events are counted for.
The MedDRA version used for reporting the study will be described in a footnote.


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If a patient reported more than one adverse event with the same preferred term, the adverse 
event with the greatest severity will be presented. If a patient reported more than one adverse 
event within the same primary system organ class, the patient will be counted only once with 
the greatest severity at the system organ class level, where applicable. 
The following summaries of adverse events will be provided for Group G and Group F:

Incidence and incidence rate of adverse events per 100 patient-years, by primary system 
organ class and preferred term. Incidence rate ratio will be presented in Group G table.
Another Group G table will be created presenting only the adverse events where the FTY 
cohort incidence rate is greater than zero while the Other DMT cohort incidence is equal 
to zero. For this table the incidence rate difference is presented instead of incidence rate 
ratio.

Incidence and incidence rate of serious adverse events per 100 patient-years, by primary 
system organ class and preferred term. Incidence rate ratio will be presented in Group G
table.

Incidence and incidence rate of death per 100 patient-years, by primary system organ class 
and preferred term. Incidence rate ratio will be presented in Group G table.

Incidence and incidence rate of adverse events leading to permanent discontinuation per 
100 patient-years, by primary system organ class and preferred term (For Group G, only 
events leading to discontinuation of corresponding initial cohort treatment (FTY720 for 
the FTY720 cohort and other DMT in the other DMT cohort) will be summarized. For 
Group F only events leading to discontinuation of FTY720 will be summarized).
Incidence rate ratio will be presented in Group G table.

Incidence and incidence rate of selected safety outcomes per 100 patient-years. Incidence 
rate ratio will be presented in Group G table.

Incidence and incidence rates of adverse events, by primary system organ class, preferred 
term, and maximum severity.

Incidence and incidence rate of adverse events with suspected relationship to study 
treatment per 100 patient-years, by primary system organ class, preferred term, and initial 
cohort treatment, Group G, Safety set only. Incidence rate ratio will be presented in Group 
G table.

Incidence rate of adverse events per 100 patient-years, by primary system organ class, 
preferred term, and first DMT corresponding to cohort assignment, Group G, Safety set 
only.

Incidence rate of serious adverse events per 100 patient-years, by primary system organ 
class, preferred term, and first DMT corresponding to cohort assignment, Group G, Safety 
set only.

Incidence and incidence rate of adverse events per 100 patient-years, by primary system 
organ class and preferred term – excluding AEs listed in Core Data Sheet (CDS).
Incidence rate ratio will be presented in Group G table.

Incidence and incidence rate of serious adverse events per 100 patient-years, by primary 
system organ class and preferred term – excluding AEs listed in CDS. Incidence rate ratio 
will be presented in Group G table.


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
Incidence rate of adverse events per 100 patient-years, by preferred term and initial cohort 
treatment – Excluding AEs listed in Core Data Sheet (CDS). Incidence rate ratio will be 
presented in Group G table.

Incidence rate of adverse events / SAEs per 100 patient-years, by primary system organ 
class and preferred term, excluding events which occurred in the first week (Days 1 to 7) / 
first 6 months (Days 1 to 180) following real first dose of initial cohort treatment. In these 
summaries all events which started during the excluded window will not be taken into 
account and the corresponding exposure time will be removed from the denominator. If, 
after removing the time interval of interest, a patient does not have any exposure within 
the study, the patient will be completely removed from this analysis. (This analysis is only 
done for Group G).

Number and percentage of patients reporting adverse events and serious adverse events 
related to the primary system organ classes 'Cardiac disorders', 'Infections and infestations', 
and 'Neoplasms benign, malignant and unspecified (incl cysts and polyps)', by time 
interval (Months 0-<3, Months 3-<6, Months 6-<9, Months 9-<12, Months 12-<24, 
Months 24-<36, Months 36-<48, >= Month 48), primary system organ class and preferred 
term for Group G, Safety set. Months will be defined using 30-day intervals, i.e., Day 1-90, 
Day 91-180, Day 181-Day 270, Day 271-Day 360, Day 361-720, Day 721-Day 1080, Day 
1081- Day 1440, >= Day 1441, whereby the onset date of the first occurrence of such 
adverse events per patient will be used to classify them into the time intervals. The 
number of active patients, i.e., who did not discontinue from the initial cohort treatment 
and had at least 1 day of exposure during the interval, will be displayed. The date of first 
dose of initial cohort treatment in the study will be used as Day 1. This will be 
summarized separately for each of the selected system organ classes. When calculating 
percentages the denominator will be defined for each event as the total number of patients 
experiencing the specific event.

An analysis as described above will be done for all AEs instead of only for a selection of 
AEs. The following time intervals will be used: Months 0 - <12, Months 12 - <24, Months 
24 - < Months 36, Months 36 - <48, Months 48 - <50. The analysis will be done for Group 
G, safety set.

Number and percentage of patients reporting bradycardia / serious bradycardia by time 
interval (Day 1-7, Day 8-30, Day 31-60 (Month 2), Day 60-91 (Month 3) etc. in 30 day 
intervals until Day 360 and then >= Day 361) for Group G, safety set. The onset date of 
the first occurrence of bradycardia / serious bradycardia per patient will be used to classify 
them into the time intervals. The number of active patients, i.e., who did not discontinue 
from the initial cohort treatment and had at least 1 day of exposure during the interval will 
be displayed. The date of first dose of initial cohort treatment in the study will be used as 
Day 1.

The time to first onset of bradycardia / serious bradycardia will be analyzed using Kaplan-
Meier curves for Group G, safety set. Patients not experiencing the event will be censored 
at their last dose date of initial cohort treatment + 45 days, day before first dose date of 
treatment after permanent switch, or cut-off date whichever is earliest (VDW variable 
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
Number and percentage of AEs/SAEs on selected safety outcomes by time interval 
(Months 0-<3, Months 3-<6, Months 6-<9, Months 9-<12, Months 12-<24, Months 24-
<36, Months 36-<48, >= Month 48) for Group G, Safety set. Months will be defined using 
30-day intervals, i.e., Day 1-90, Day 91-180, Day 181-Day 270, Day 271-Day 360, Day 
361-720, Day 721-Day 1080, Day 1081- Day 1440, >= Day 1441, whereby the onset date 
of the first occurrence of such adverse events per patient will be used to classify them into 
the time intervals. The number of active patients, i.e., who did not discontinue from the 
initial cohort treatment and had at least 1 day of exposure during the interval, will be 
displayed. The date of first dose of initial cohort treatment in the study will be used as Day 
1. This will be summarized separately for each of the selected system organ classes. When 
calculating percentages the denominator will be defined for each event as the total number 
of patients experiencing the specific event.

The time to first onset of cancer will be analyzed using Kaplan-Meier curves for Group G, 
safety set. AEs will be identified as cancer by using the same excel sheet that is being used 
to define the subgroup of patients who had an AE categorized as cancer (see section 4.5.1). 
Patients not experiencing the event of interest will be censored at their last dose date of 
initial cohort treatment + 45 days, day before first dose date of treatment after permanent 
switch, or cut-off date whichever is earliest (VDW variable CUTO_CO).
 
 
 
 
Subgroup analyses of adverse events and selected safety outcomes
Incidence rates per 100 patient years of AEs/SAEs by primary SOC and preferred term will be 
provided for all subgroups as defined in Section 4.5.1 above.
Incidence rates per 100 patient years of selected safety outcomes (risks) will be provided for 
the following subgroups (see Section 4.5.1 for definition)

Patients in  naïve to any prior MS DMT

Patients previously treated with any MS DMT

Patients never treated with FTY720

Patients in the FTY720 cohort split by subgroups based on the type of MS therapy 
previously used.
For the first three subgroups incidence rate ratio will also be presented.
Incidence rate, incidence rate ratio and incidence rate difference calculation
The incidence rate expressed per 100 patient-years of the at-risk population is calculated as: 
the number of patients experiencing at least one event in a particular category, over the total 
patient-years of the “at risk” population for that event multiplied by 100. 


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For patients who have that adverse event, the time at risk is the time from Day 1 (from Group 
G / Group F) to the first onset date of that adverse event. For patients who did not have that 
adverse event, the time at risk as defined in Section 4.3.3 is used. 
The incidence rate ratio (IRR) is calculated by dividing the incidence rates of two cohorts for 
a particular AE term/category. It is only calculated if both incidence rates are >0.
In cases where the FTY720 incidence rate is >0 and the Other DMT Cohort incidence rate is 
equal to 0 an additional analysis will be carried out where the incidence rate difference will be 
calculated.
See Section 5 for details on incidence rate, incidence rate ratio, incidence rate difference and 
the corresponding 95% confidence intervals calculations. 
About selected safety outcomes
One of the main objectives of the PASSAGE studies is to investigate the incidence of selected 
safety outcomes. Those selected safety outcomes contain Risk management plan (RMP) risks 
and some additional PASSAGE specific risks. All PASSAGE selected safety outcomes (RMP 
risks and additional ones) are defined in the program level Case Retrieval Sheet (CRS) which 
will be finalized prior to database lock. 
Link to VDW: Adverse events risk data are available in the VDW Risk panel (AAEVRISK).
Pooled analyses of adverse events and medical history
Medical history records (i.e., all events reported on the medical history CRFs, which occurred 
on initial cohort treatment and within at most 180 days prior to FIRSMD1O reported as 
medical history) will be pooled with adverse event records and then the frequencies (total 
number and percentage of patients) and the incidence rates per 100 patient years for AEs will 
be generated for Group G Safety Set. Any partial condition start dates will be imputed using 
the rules of AE start date imputation. 
The following summaries for Group G, safety set will be generated:

Incidence rate by primary system organ class, preferred term and initial cohort treatment

Incidence rate of selected safety outcomes (risks) by initial cohort treatment
Cox proportional hazard regression model
A comparative analysis to estimate adjusted Hazard Ratios (HR) using a Cox proportional 
hazards regression model will be performed. The analysis will be done for all selected safety 
outcomes of the RMP category, respectively, using exact method for handling ties in failure 
time. 
The HRs and their associated confidence intervals will be estimated by means of a 
proportional-hazards model. The dependent variable is time-to-first occurrence of a particular 
selected safety outcome while initial cohort treatment, age at baseline, gender and study will 
be used as covariates in the model. This analysis will be provided for pooled analysis.


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See section 5 for details on the calculations of the cox proportional hazard regression model.
Analysis of adverse events details for subgroup = Patients who had an AE categorized as 
cancer
For the subgroup of patients who had an AE categorized as cancer the adverse event details 
will be tabulated for Group G, safety set, by initial cohort treatment. The number and 
percentage of cancers by preferred term will be presented. Also the number and percentage of 
the action taken category and the relationship with MS therapy will be displayed. Each 
category for action taken category will be counted once per patient. For action taken multiple 
answers for one AE are possible. Relationship with MS therapy will be counted once per 
patient with worst category. Additionally the summary statistics of time to onset of first 
cancer (in years) will be shown.
Time to onset of AE of MS relapse
The time to onset of and adverse event of MS relapse will be presented in categories (< 1 
month, >=1 month and <6 months, >=6 months and < 1 year, >=1 year and < 2 years, >= 2 
years) by initial cohort treatment and by seriousness (AE or SAE) for Group G, safety set.
Each category for time to onset of MS relapse is counted only once per patient. Multiple MS 
relapses from one patient that fall into different time categories are each counted in their 
respective category. The total number of patients with relapses will also be tabulated.
Summary of action taken for AE hypertension
The number and percentage of each action taken information from the eCRF AE page will be 
displayed by initial cohort treatment, for Group G, safety set. The number and percentage of 
preferred terms for hypertension AEs will be presented. Each action taken category is counted 
only once per patient. For action taken multiple categories for one AE of hypertension are 
possible. Additionally the total number of patients with hypertension AE will also displayed.
4.13.3
Laboratory data
4.13.3.1 Abnormal liver function tests
The number and percentage of patients with newly occurring abnormal liver function test
values, as defined in Appendix D of this document,  after Day 1 (from data per general safety 
rules) will be summarized for the Group G, safety set, by initial cohort treatment and Group F, 
safety set, by study. In order to present newly occurring events, the number and percentage of 
patients will be calculated based on the number of patients who have the specified liver 
function test(s) on or after first dose date of initial cohort treatment in study, the 
corresponding upper limit of normal(s), and either normal or missing result(s) for the 
specified liver function test(s) prior to first dose of initial cohort treatment in the study. The 
normal limit is set based on local lab criteria. This analysis includes Hy's Law cases.
Liver function tests include: alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase (ALP), and total bilirubin (TBL). 
The following rules will be applied for the summary tables:


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For liver enzymes only those values where the SI value is available or can be calculated and 
the normal range is also available in SI units or can be calculated, and the SI upper normal 
limit is higher than the SI lower normal limit will be used.
All patients with newly occurring abnormal liver function tests will be listed.
4.13.3.2 Clinically notable laboratory abnormalities
The number and percentage of patients with newly occurring clinically notable laboratory 
results on or after Day 1 (from data per general safety rules) for leukocytes and lymphocytes 
will be presented by initial cohort treatment for the Group G, safety set and Group F, safety 
set, by study. Laboratory results will be converted to SI units for this summary. Criteria for 
notable laboratory abnormalities are provided in Appendix D of this document. Laboratory 
local reference normal ranges will not be used in the analysis instead clinical notable 
abnormality criteria are used.
In order to present newly occurring events, the number and percentage of patients will be 
calculated based on the number of patients who have at least one lab assessment on or after 
first dose date of initial cohort treatment in study for the specified lab test and either non-
notable or missing lab assessment prior to first dose of initial cohort treatment in the study. If 
the baseline measurement is missing, all abnormal lab measurements after baseline should be 
reported. 
For WBC and absolute lymphocytes count reported values which are outside the reported 
normal ranges and which can be converted to SI units will be used. 
All patients with notable abnormalities will be listed.
4.13.3.3
Other laboratory data
Absolute values and changes from baseline of total cholesterol and HDL cholesterol will be 
summarized by visit for Group G, safety set. Values for corresponding visits will be derived 
by a visit windowing approach, detailed in Section 4.15.
4.13.4
Routine vital signs
For routine vital sign measurements (excluding first dose monitoring assessments), the 
number and percentage of patients with at least one value after Day 1 (from data per general 
safety rules) satisfying clinically notable criteria will be summarized for the Group G, safety 
set, by initial cohort treatment and Group F, safety set, by study. The criteria of notable vital 
signs are provided in Appendix E of this document.
All patients with notable abnormalities will be listed. 
4.13.5
First dose monitoring (Group F only)
Note that only the first dose monitoring which starts on the first dose date of FTY720 in the 
study, but which may extend past the first dose date of FTY720 in the study, is considered 
data related to the first initiation of FTY720. Other first dose monitoring is conducted at re-
initiation and summarized separately for patients with more than one first dose monitoring.   


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The hourly post-dose timepoints will be derived based on windowing the time of assessment –
first dose administration time. In the case where either time is missing and the hours post-dose  
are labeled in the CRF (only labeled in D2403 vital signs CRF), the CRF post-dose label will 
be used to determine the timepoint.  
Window
Timepoint
<1 minute
Pre-dose
1 minute to 1.5 hours
1 hour post-dose
>1.5 hours to 2.5 hours
2 hours post-dose
>2.5 hours to 3.5 hours
3 hours post-dose
>3.5 hours to 4.5 hours
4 hours post-dose
>4.5 hours to 5.5 hours
5 hours post-dose
>5.5 hours to 6.5 hours
6 hours post-dose
For example, an assessment taken 1 hour and 45 minutes after first dose administration will be 
classified as a 2 hours post-dose assessment. In the case where multiple assessments within a 
post-dose hour are available, the assessment closest to the expected time will be used for 
hourly summary by post dose hour. However, the lowest pulse should be based on all post 
dose observations no matter if the actual collection is closest to the expected time or not. All 
data will be presented in the listing.
4.13.5.1 First dose monitoring of vital signs 
Hourly vital signs are collected on first dose administration monitoring pages for first dose of 
FTY720 in the study and re-initiation of FTY720 after interruption if applicable. 
The Day 1 sitting pulse, sitting systolic, and sitting diastolic blood pressure will be 
summarized at hourly post-dose  time points for up to 6 hours (1hour post-dose, 2 hours post-
dose, ..., 6 hours post-dose), by study, for the Group F, safety set. Summary statistics will be 
provided for the pre-dose value, the post-dose value, and change (post-dose minus pre-dose). 
The time in hours during first dose monitoring of the lowest pulse occurring post first dose of 
FTY720, and the lowest pulse (bpm) observed during first dose monitoring will be 
summarized for the Group F, safety set, by study. Only data from first FTY720 initiation are 
summarized.
A line plot of the mean pulse (bpm), along with corresponding standard deviation, during the 
6 hours post-first dose administration monitoring will be presented for the Group F, safety set, 
by study. Only data from the first FTY720 initiation will be summarized.
4.13.5.2 First dose monitoring procedures
The FTY720 first dose monitoring procedures based on the first FTY720 initiation will be 
summarized on the Group F, safety set, by study. The number and percentage of patients with 


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first dose monitoring data will be reported out of the total number of patients in Group F, 
safety set. For all first-dose monitoring related frequencies, the percentage of patients reported 
will be calculated based on the number of patients with first dose monitoring data as the 
denominator. The same analysis will be repeated for first FTY720 re-initiation. There should 
be at least 45 days between the date of re-initiation of FTY and the last dose of FTY prior to 
re-initiation. 
The following will be summarized:

The number and percentage of patients with first dose monitoring data collected 
retrospectively and data collected prospectively will be reported. For patients with prior 
FTY720 that can be considered as ‘Initial cohort treatment ongoing at study entry’, first 
dose monitoring data is considered retrospective. Otherwise, first dose monitoring data is 
considered prospective. This will only be summarized for first FTY720 initiation.

Whether a cardiologist consultation was conducted before starting FTY720. In study 
D2403, question was added during eCRF Amendment 1. So data are only available for 
second part of the patients enrolled post amendment implementation.

Whether a patient required extended cardiac monitoring after the first 6 hours and whether 
a patient required >=12 hours and <=24 hours or >24 hours and <=48 hours post first dose 
monitoring time. In case the first dose time is missing the pre-dose ECG/vital sign
measurement time + 5 minutes from the same day will be used, if available. This summary 
will be based on actual first dose monitoring times rather than responses to the CRF 
question on dose monitoring CRF pages. Even though the question of extended 
monitoring beyond 6 hours post dose was asked directly in CRF Amendment for 2403, the 
data should be derived for both studies. If patient has any first dose monitoring data 
collected after 6 hours post dose, it will be considered as extended monitoring. 

Whether a patient had symptomatic or treated bradycardia: In CRF for D2406 and 
previous CRF for D2403, the question “Did the patient have symptomatic or treated 
bradycardia?” exists in the CRF. For current eCRF of D2403, this corresponds to the 
cardiac event specified on CRF page of ‘Fingolimod first dose extended/overnight 
monitoring procedure”. In yet another CRF amendment, this question was split into two 
questions “Was the bradycardia symptomatic?” and “Was the bradycardia treated?”. The 
responses from these three questions will be combined to determine whether a patient had 
symptomatic or treated bradycardia.
The corresponding variable, for both studies, will be taken from the VDW. If no 
information about a symptomatic or treated bradycardia can be obtained then the question 
"Did the patient experience a cardiovascular event during the first dose observation 
period?" from the CRF will be used to determine the answer categories "No" or
"Unknown". This approach will be used for D2403 and D2406.

The number and percentage of patients with new or worsening ECG abnormalities 
reported over all post-dose hours related to the first FTY720 initiation: the data from old 
CRF for question ‘Was any new or worsening ECG abnormalities recorded?’ and from 
new CRF for post dose question ‘Are new or worsening ECG abnormalities present?’ are 
combined together on summarizing results. If subject has any answer of yes on the 
question, the overall evaluation is ‘Yes’; else if there is any answer of ‘No’, then the 


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overall evaluation is ‘No’. If all answers to this question is missing, and from new CRF 
data it’s marked that post-dose evaluation was not done on any post-dose hours, the 
overall evaluation is ‘Not done’. Otherwise, the overall evaluation is set as ‘Unknown’.

A listing of patients requiring extended cardiac monitoring >=12 hours after first dose 
administration of FTY 720 will be provided for the single study CSRs.
4.13.6
Ophthalmic and dermatological examination
For FTY720 treated patients, an ophthalmic examination could be performed before FTY720
initiation and 3 to 4 months later for the purpose of detecting macular edema. Examinations
performed up to 45 days prior to fingolimod treatment initiation are also acceptable. In 
diabetic patients, additional ophthalmologic examinations are performed at the time they 
discontinued FTY720. Additionally, any patient having new visual symptoms should have an 
ophthalmic examination irrespective of the MS treatment the patient is taking.
The ophthalmic examination data will be summarized for Group F, safety set, separately for 
each study and combined. The visual acuity assessment result (normal, abnormal), as assessed 
by the Investigators, will be summarized with number of patients and percentages in shift 
tables comparing the status before FTY720 initiation to each evaluated time point and the 
worst post FY720 initiation result, separately for each eye. Presence of macular edema (no, 
yes, unknown, other abnormality) will be summarized by number and percentage of patients
who develop a macular edema during the course of treatment with FTY720. The analyses will 
be presented for the right eye and left eye separately. Additionally they will be analyzed by an 
overall category which summarizes the results from left and right eye, using each patient's 
worst assessment.
A dermatological examination could be performed for a patient (irrespective of the MS 
therapy they are on) at baseline, at the time of change in MS therapy, and at the end of the 
study. This examination has to be conducted by a certified dermatologist or a physician 
experienced in dermatological evaluation for the purpose of detecting skin malignancies.
The dermatological examination results will be summarized for Group G, safety set by 
number and percentage of patients per visit and category (normal, abnormal non-cancerous, 
abnormal pre-cancerous, abnormal cancerous lesion) in shift tables showing baseline results 
versus the results at each time interval. 
Data will be taken from the single study databases, since they are not covered by the VDW.
4.14
Other assessments
4.14.1
D2403 Patient Reported Outcomes
Patients of this sub-study of study D2403 will be identified by having consented to participate 
in the Patient Reported Outcomes (PRO) sub-study.
The following will be summarized:

Patient disposition will be summarized by cohort (Group G, enrolled set)


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
Patient demographics, MS history and MS treatment(s) preceding fingolimod or 
comparator initiation will be summarized by cohort (Group G, safety set)

Comparison of mean change in the patient-reported disability level by visit and cohort 
(Group G, safety set)

MS Impact Scale (MSIS-29): Summary statistics of absolute values and change from 
baseline in summary scores (Physical impact, Psychological impact) will be presented 
by visit and cohort (Group G, safety set)

Work Productivity and Activity Impairment Questionnaire: General Health 
(WPAI:GH): Summary statistics of absolute values and change from baseline in 
summary scores (Absenteeism, Presentism, Work productivity loss, Activity 
impairment) will be presented by visit and cohort (Group G, safety set)

Patient Reported Indices of Multiple Sclerosis (PRIMUS) – Activities: Summary 
statistics of absolute values and change from baseline in PRIMUS activity scale score 
will be presented by visit and cohort (Group G, safety set)

Abbreviated Treatment Satisfaction Questionnaire for Medication (TSMQ-9): 
Summary statistics of absolute values and change from baseline in summary scores 
(Effectiveness, Convenience, Global Satisfaction) will be presented by visit and cohort 
(Group G, safety set)

Treatment preference (for patients who are newly treated with fingolimod, yet have 
been on previous disease-modifying therapy) will be summarized with number and 
percentage at month 6 for Group F, safety set

Annualized relapse rates for Group G, effectiveness set.
PRO manuals
MSIS-29
The MS IMPACT SCALE (MSIS) in this study contains 29 items with 5 possible outcomes 
for each item: 1 (Not at all), 2 (A little), 3 (Moderately), 4 (Quite a bit) and 5 (Extremely). 
For the summary of MSIS data, two summary scales, physical impact score (20 items) and 
psychological impact score (9 items) will be calculated according to the scoring manual 
provided by Hobart et al. in Improving the evaluation of therapeutic interventions in multiple 
sclerosis (originally published in 1995, updated in 2007). Higher summary scores indicate 
worse health state.  The detailed scoring algorithms are as following: 
Physical impact score 
The physical impact score is computed by summing items number 1-20 inclusive. This score 
can then be transformed to a score on a scale of 0 -100 using the formula below: transformed 
score = 100 x (observed score minus lowest possible score)/ (maximum possible score minus 
minimum possible score).  For example, the MSIS-29 physical scale where min possible score 
= 20, max possible score = 100, range = (100 – 20) = 80 then physical impact score=100 x 


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(observed score - 20) /(100 – 20). Note that transforming scores to have a range of 0 – 100 is 
for ease of interpretation. It does not affect the properties of the scale.
Psychological impact score
The psychological score is computed by summing items number 21-29 inclusive. This score 
can then be transformed to a score on a scale of 0-100 using the formula below: 100 x 
(observed score - 9) / (45 – 9).
Missing data 
For respondents with missing data, but where at least 50% of the items in a scale have been 
completed, a respondent–specific mean score computed from the completed items can be used 
for imputation. For example, consider person X who has completed 15 items in the physical 
scale. Sum the completed items and divide it by 15 to get person X’s respondent–specific 
mean score. Then use this value as the score for each of the missing 5 items. Then generate a 
total score as usual by summing the values of the 15 completed items and the 5 imputed items. 
Note: respondents must have completed a minimum of 10 items in the physical scale, or 5 
items in the psychological scale to use this imputing method.
If fewer answers are provided, the corresponding scores will not be calculated.
WPAI:GH
The WPAI questionnaire is an instrument that measures the impact of health problems on the 
ability to work and perform regular activities during the past 7 days. WPAI yields 4 types of 
scores: Absenteeism (work time missed), Presentism (impairment at work/reduced on-the-job 
effectiveness), work productivity loss (overall work impairment/absenteeism plus presentism) 
and Activity impairment. The WPAI consists of six questions:
Q1=currently employed (y/n)
Q2=hours missed from work due to health problems
Q3=hours missed from work due to other reasons
Q4=hours actually worked
Q5=degree health affected productivity while working (0 to 10)
Q6=degree health affected productivity in regular unpaid activities (0 to 10)
The recall period for questions 2 to 6 is seven days. The following scores will be calculated:
Absenteeism (percent work time missed due to health) = Q2/(Q2 + Q4)
Presentism (percent impairment while working due to health = Q5/10
Work productivity loss (percent overall work impairment due to health): Q2/(Q2 + Q4) + (1 –
Q2/(Q2 + Q4)) x (Q5/10)
Activity impairment: Q6/10 
Multiply scores by 100 to express percentages.
PRIMUS-Activities


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The Subject Reported Indices of Multiple Sclerosis PRIMUS - activities scale will be 
calculated and analyzed according to the scoring manual provided by Galen Research Limited, 
2007.
The activities scale in this study contains 15 items. Each of the 15 items will be given a score 
of 0 (able to do on own without difficulties) or 1 (able to do on own with difficulties) or 2 
(unable to do on own). All 15 item scores will be summed to obtain a total score ranging from 
0 (good) to 30 (poor), which is the PRIMUS activities scale score. Higher summary scores 
indicate worse health.
In case of missing item scores while calculating the scale score, the following rule applies: if 
more than 20% (i.e., three) of the item scores are missing, the scale score will not be 
calculated and set to missing. If no more than 20% of the item scores are missing, the scale 
score will be imputed as the average of the non-missing item scores multiplied by 15.
TSQM-9
The Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) is an abbreviated 9-
item questionnaire derived from the TSQM without the five items of the side effects domain.  
The TSQM-9 domain scores range from 0 to 100 with higher scores representing higher 
satisfaction on that domain.
The scales of the TSQM-9 include the effectiveness scale (questions 1 to 3), the convenience 
scale (questions 4 to 6) and the global satisfaction scale (questions 7 to 9). The higher 
summary scores indicate better satisfaction with study drug. 
TSQM-9 Scale scores will be computed by adding the items loading on each factor.  The 
lowest possible score is subtracted from this composite score and divided by the greatest 
possible score minus the lowest possible score. This provided a transformed score between 0 
and 1 that should be multiplied by 100 as described below.
Note that only one item may be missing from each scale before the subscale should be 
considered invalid for that respondent.
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
CONVENIENCE: 
Score = {[(sum of items 4- 6) – 3] / 18} * 100
If only one item is missing, Score = {[(sum of available items in 4-6) – 2] / 12} * 100
GLOBAL SATISFACTION: 
Score = {[(sum of items 7- 9) – 3] / 14} * 100
If only one item is missing:
Item 7 or 8 missing:  Score = {[(sum of available items in 7 - 9) – 2] / 10} * 100
Item 9 missing:           Score = {[(sum of items in 7 and 8) – 2] / 8} * 100


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4.14.2
D2403 sub-studies
The number and percentage of patients in the respective sub-studies will be summarized for 
Group G, Enrolled set, for D2403.
Pulmonary sub-study
For all patients in the pulmonary sub-study the following analyses will be done:

Patient disposition will be summarized by cohort (Group G, enrolled set)

Demographics will be summarized by cohort (Group G, safety set)

Medical history will be summarized by cohort (Group G, safety set)

Exposure during initial cohort treatment by cohort (Group G, safety set)

Summary statistics of absolute values and changes from baseline of pulmonary 
function test data (FEV1, Percentage of predicted FEV1, FVC and DLCO) will be 
presented by visit for each cohort (Group G, safety set) 
o
Percentage of predicted FEV1 is obtained as a percentage of FEV1 relative to 
the predicted normal value. The predicted normal value is calculated as 
follows:

Male:   (4.30 x Height in meters) – (0.029 x Age in years) – 2.49

Female:  (3.95 x Height in meters) – (0.025 x Age in years) – 2.60

If Race = Black or Ethnicity = Indian then the predicted normal given 
by the formulae above will be multiplied by 0.9.
Patients of this sub-study will be identified by having consented to participate in the 
pulmonary sub-study.
Canadian sub-study
For all patients in the Canadian sub-study the following analyses will be done:

Patient disposition will be summarized by cohort (Group G, enrolled set)

Demographics (also education level, employment and occupation) will be summarized 
by cohort (Group G, safety set)

Medical history will be summarized by cohort (Group G, safety set)

Exposure during initial cohort treatment by cohort (Group G, safety set)

Summary of MS relapse characteristics by cohort (Group G, Effectiveness set)

Annualized relapse rates by first DMT corresponding to cohort assignment (Group G, 
Effectiveness set)

Multiple sclerosis disease history at baseline (Group G, Safety set)

Box-plot of change from baseline for EDSS score by visit (Group G, Effectiveness set)


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
Summary statistics of absolute values and changes from baseline in serum levels of 
Vitamin D25 and LDL will be presented by visit and cohort (Group G, safety set)

Summary of Resource Utilization Questionnaire (RUQ) presented by visit and cohort 
(Group G, safety set).

MS-TAQ: The MS-TAQ questionnaire is a self-administered tool to identify barriers 
to adherence for MS patients taking DMTs. The MS-TAQ questionnaire contains 30 
questions in three subscales, DMT-Barriers (Range: 0-39), DMT-Side Effects (Range: 
0-40), DMT-Coping Strategies (Range: 0-7). Summary statistics of the subscales and n 
and percentage for the remaining questions will be presented by visit for Group G, 
safety set. The subscales are calculated as follows:
o
DMT-Barriers = sum of items 7 to 19. Answers are weighted as follows: "Not 
important at all" = 0, "A little important" = 1, "Moderately important" = 2, 
"Extremely important" = 3. 
o
DMT-Side Effects = sum of items 20 to 29. Answers are weighted as follows: 
"Never" = 0, "A few times" = 1, "About half the time" = 2, "Most of the time" 
= 3, "All or nearly all the time" = 4.
o
DMT-Cope = sum of items 30 to 36. Answers are weighted as follows: "No" = 
0, "Yes" = 1.

Number and percentage of patients having received Vitamin-D supplementation at 
least once (yes/no) and summary of highest total daily dose (Group G, Safety set)
All patients from Canada will be taken into account in this sub-study analysis.
Cardiac sub-study
Patients in the cardiac-sub study will be identified by medical review of criteria relevant for 
cardiac sub-study before DB lock. The following summaries will be done for Group F, safety 
set:

Patient disposition will be summarized (Group F, enrolled set)

Demographics including Framingham risk score

Medical history 

Incidence of serious cardiovascular events (see Appendix Table K-1 for definition)
will be summarized with number and percentage by preferred term Corresponding 
exact 95% confidence interval (Clopper-Pearson, 1934) will be calculated.

Summary statistics in absolute values and change from baseline in blood pressure and 
heart rate will be presented by visit

Summary statistics in absolute values and change from baseline in total cholesterol 
and HDL will be presented by visit

Incidence of any new abnormal ECGs will be summarized with number and 
percentage.


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4.14.3
Pool of D2409 and D2403 cardiac sub-study data
In order to gain more information, data from the D2409 will be pooled with data from the 
cardiac sub-study of D2403 study in which patients will be followed similarly to the D2409 
study.
The following summaries will be done for Group F, safety set, if not specified otherwise:

Patient disposition will be summarized (Group F, enrolled set)

Demographics including Framingham risk score and European CVD risk score

Medical history 

Incidence of serious cardiovascular events (see Appendix Table K-1 for definition)
will be summarized with number and percentage by preferred term. Corresponding
exact 95% confidence interval (Clopper-Pearson, 1934) will be calculated.

Incidence of serious cardiovascular events (as described above) will be summarized 
with number and percentage by preferred term for Group G, safety set, stratified by 
Framingham risk score category (<=median, >median). The median used for 
categorization will be calculated over the Framingham risk score of all pooled cardiac 
patients with FTY as initial cohort treatment. The comparison cohort (Other DMT) 
will contain all Other DMT patients from D2403 and D2406 from Group G, safety set.

Summary statistics in absolute values and change from baseline in blood pressure and 
heart rate will be presented by visit

Summary statistics in absolute values and change from baseline in total cholesterol 
and HDL will be presented by visit

Incidence of any new abnormal ECGs will be summarized with number and 
percentage.
Framingham risk score calculation
The Framingham risk score will be derived based on the risk factors sex (m/f), age (years), 
(treated) systolic blood pressure (mmHg), smoking (yes/no), diabetes (yes/no), HDL (mg/dL)
and total cholesterol (mg/dL) following the approach from D'Agostino et al., 2008. The tables 
G-1 and G-2 (see Appendix G) present the score sheets to estimate the risk of cardiovascular 
disease (CVD) events for women and men respectively. Depending on the category of each 
risk factor risk points are assigned. According to the total sum of all risk points of a patient 
the corresponding CVD risk (%) is determined (see tables G-3 and G-4, Appendix G). 
In case of missing values for total cholesterol or HDL the following imputation rules will be 
used. Missing total cholesterol values with be imputed by 170 mg/dL and missing HDL 
cholesterol by 50 mg/dL. This approach follows Samuel Cykert et al. (2019).
The diabetes variable will be derived by using the medical history of the patient using the 
MedDRA High Level Term "Diabetes mellitus (incl subtypes)". To derive if systolic blood 
pressure was treated a patient must have a medical history of hypertension and the 
concomitant medications treating the hypertension (see Appendix table H-1 for list of 
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All risk factores will be assessed at baseline (last assessment before or on day of entering 
respective cardiac sub-study (for D2403 cardiac sub-study and D2409), last assessment before 
or on day of first Other DMT administration within the study for all D2403 and D2406 Other 
DMT cohort patients).
European CVD risk score calculation (SCORE - Systematic Coronary Risk 
Estimation)
The SCORE system estimates the 10 year risk of fatal CVD in Europe. Its applicability to 
non-Caucasian populations has not been examined (Piepoli MF, Hoes AW, Agewall S, et al. 
2016). It will be derived based on the same risk factors and using the same time point as the 
Framingham risk score with the exception of diabetes and HDL. The score will be derived for
Group F patients. The total cholesterol value will used using mmol/L as unit. Additionally to 
the risk factors mentioned previously patients are categorized into low and high risk countries 
and the respective low/high risk chart has to be used in derivation of the score. The following 
countries are defined as being in the low risk category: Andorra, Austria, Belgium, Cyprus, 
Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, 
Malta, Monaco, The Netherlands, Norway, Portugal, San Marino, Slovenia, Spain, Sweden, 
Switzerland and the United Kingdom. All other European countries are categorized as high 
risk countries. For patients from non-european countries are analyzed as if their country 
would be part of the high risk category. The low risk chart (see Appendix J-2) and the high 
risk chart (J-1) will be used to calculate the European CVD risk score. 
4.14.4
D2409 study
For all patients in the D2409 study the following summary analysis will be done:

Incidence of serious cardiovascular events (see Appendix Table K-1 for definition) 
will be summarized with number and percentage by preferred term. Corresponding 
exact 95% confidence intervals (Clopper-Pearson, 1934) will be calculated.
For this analysis D2409 patients will be compared to the population of D2406 patients in 
Group F who had no serious CV event during first dose monitoring (i.e. during Day 1 and 
Day 2 of first dose of FTY or re-initiation).
The following data will be listed for D2409 patients:

Premature discontinuation from study

Protocol deviations

Demography including Framingham risk score and European CVD risk score

Relevant medical history and co-morbidities

Multiple sclerosis history

Multiple sclerosis disease modifying therapy

Study cohort treatment exposure

Concomitant medications and significant non-drug therapies


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
Multiple sclerosis relapses

EDSS scores

Laboratory assessments

Fingolimod first dose monitoring procedures and observations

ECG 

Ophthalmologic assessments
4.15
Visit windows
Visit windows will be used to present summary statistics by visit. If for a specific analysis the 
respective data is part of the data warehouse corresponding remapped visit data is used. If this 
is not the case or the visit windows defined in this document differ from the VDW the data
will be remapped using an approach that is consistent with the general approach used in the 
data warehouse. Visit windows will only be used for post-baseline data.
The following table displays the visit windows that will be applied.
Table Visit-windows
For RUQ, MS-TAQ and EDSS
Visit
Start day (time)
Target Day (time)
End day (time)
VWINN
Month 3
2
91
136
1
Month 6
137
182
273
2
Month 12
274
365
547
3
Month 24
548
730
912
4
Year 3 (M36)
913
1095
1278
5
Year 4 (M48)
1279
1461
1643
6
Year 5 (M60)
1644
1826
2008
7
For ophthalmologic examination1, TSQM-9 and treatment preference
Visit
Start day (time)
Target Day (time)
End day (time)
VWINN
Month 6
2
182
363
2
For dermatological examination1
Month 6
2
182
273
2
Month 12
274
365
547
3
For pulmonary function test, total cholesterol, HDL cholesterol, Vitamin D, LDL, systolic blood 
pressure, diastolic blood pressure and heart rate
Visit
Start day (time)
Target Day (time)
End day (time)
VWINN
Month 12
2
365
547
3
Month 24
548
730
912
4
Year 3 (M36)
913
1095
1278
5


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Year 4 (M48)
1279
1461
1643
6
Year 5 (M60)
1644
1826
2008
7
For patient-reported disability, MSIS-29, WPAI-GH, PRIMUS
Month 6
2
182
273
2
Month 12
274
365
547
3
Month 24
548
730
912
4
Year 3 (M36)
913
1095
1278
5
Year 4 (M48)
1279
1461
1643
6
Year 5 (M60)
1644
1826
2008
7
- For Group G Day 1 is defined as the first dose day of study medication within the study.
- For Group F Day 1 defined as the first dose day of FTY within the study.
- If a patient has multiple visits within the same visit window the one closest to the target day will be chosen. If 
both visits have the same distance from the target day the latter one will be chosen.
- This visit windowing approach will only be used for summary statistics.
- 1 If a patient has multiple values within the same visit window the worst value is used.
- For Group G: Last assessment prior to or at first dose in study is used as baseline.
- For Group F: Last assessment prior to or at first dose of FTY in the study is used as baseline.
5
General statistical methodology
(Exposure adjusted) incidence rate and 100*(1-α)% confidence interval
It will be assumed that for each of n patients in the study, the time tj (j=1,...,n) to the first 
occurrence of a certain event is observed, or if the event was not experienced, the (censored) 
time to the end of the observation period. The sequence of first occurrences of an event will 
be modeled to follow approximately a Poisson process with constant intensity θ. The rate 
parameter θ will be estimated as λ=D/T, where 
and D is the number of patients with at least one event. Conditionally on T, an exact 100*(1-
α)% confidence interval for a Poisson variable with parameter θT and observed value D can 
be obtained based on (Garwood, 1936), from which an exact 100*(1-α)% confidence interval 
for D/T will be derived as follows (Sahai, 1993; Ulm, 1990):
Lower confidence limit   
for D>0, 0 otherwise,
Upper confidence limit 
Where 
is the αth quantile of the Chi-square distribution with k degrees of freedom.



n
j
jt
T
1
T
c
L
D
2
,2
/
5.0


T
c
U
D 2
2
,2
/
1
5.0




k
c ,



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(Exposure adjusted) incidence rate ratio and 100*(1-α)% confidence interval
Assuming D1 and D0 denote the number of subjects with event in active and reference group, 
respectively, and T1 and T0 the corresponding total time at risk. The incidence rate ratio is 
then calculated as IRR = IR1 / IR0 where IR1 = D1/T1 and IR0 = D0/T0 following Sahai and 
Khurshid (1993).
An exact 95% CI (LIRR ; UIRR) for IRR will be obtained by conditioning on the total number 
of events observed in the two groups d = D1 + D1.
Lower confidence limit: 
Upper confidence limit: 
where LBin and UBin can be produced via the following formulae:
and 
1
))
1
(
2
,
2
,2
/
(
1
1
1
1
1
1













D
d
D
Bin
F
D
D
d
L

and 
1
))
(
2
),
1
(
2
,2
/
1(
1
1
1
1
)1
(
1














D
d
D
Bin
F
D
D
d
U

.
(Exposure adjusted) incidence rate difference and 100*(1-α)% confidence 
interval
Using the same notation as above the difference between two exposure adjusted incidence 
rates can be estimated by   = 	

 −

 . Using normal approximation the corresponding (1-
α) confidence interval for  is defined by 	

 −

 ± / where  = 

 +

 . This 
approach follows G. F. Liu et al., 2006. 
Cox proportional hazard regression model
Time to first particular selected safety outcome will be analyzed with a Cox proportional 
hazards regression model. The null-hypothesis will be H0:  λFTY(t) / λOther DMT(t) = 1, where 
λ(t) is the hazard function for the failure time of patients treated with FTY720 and other DMT, 
respectively. 
The explanatory variables are age at baseline, gender, study and duration of disease since 
diagnose at study start (in years). The SAS procedure PHREG will be used with the following 
SAS code:
  proc phreg data=aaa;
    class trt(order=internal) gender study;
    model aval*cnsr(1)=trt gender study age dur / rl ties=exact;
    contrast "FTY720 vs other DMT" trt 1 /estimate=exp;
1
0
)
1(
T
L
T
L
L
Bin
Bin
IRR


1
0
)
1(
T
U
T
U
L
Bin
Bin
IRR




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   run;
where aval
= time to first particular selected safety outcome
cnsr
= data are censored if cnsr = 1
trt
= treatment (FTY720, other DMT)
gender = sex (male, female)
study
= study patient is participating in (D2403, D2406)
age
= age at screening, continuous
dur     = duration of disease at study start
Results will be presented with the hazard ratio for FTY720/other DMT and associated 95% 
confidence interval and two-sided p-value. P-value will be obtained from the Wald chi-
squared statistic testing the null-hypothesis that the parameter estimate for the respective 
treatment effect is 0 (then the hazard ratio is exp(0) = 1).
No check for the validity of proportional hazards assumptions will be done.


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6
Reference list
Atkinson MJ, Sinha A, Hass SL et al. (2004) "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, 2-12.
Hobart J, Lamping D, Fitzpatrick R, et al. (2001). "The Multiple Sclerosis Impact Scale 
(MSIS-29) A new patient-based outcome measure", Brain 124, 962-973.
Twiss J, Doward LC, McKenna SP, Eckert B, (2010). "Interpreting scores on multiple 
sclerosis-specific patient reported outcome measures (the PRIMUS and U-FIS)", Health and 
Quality of Life Outcomes 8:117.Appendices.
C. J. Clopper, E. S. Pearson. (1934). "The use of confidence or fiducial limits illustrated in the 
case of the binomial", Biometrika 26, 404–416.
Garwood, F. (1936). "Fiducial Limits for the Poisson Distribution", Biometrika, Vol. 28, No. 
3/4, December 1936, pp. 437-442.


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Sahai, H. and Khurshid, A. (1993a). "Confidence intervals for the mean of a Poisson 
distribution: A review", Biometrical Journal, 35,857–67.
Ulm K. (1990). "A Simple method to calculate the confidence interval of a standardized 
mortality ratio", American Journal of Epidemiology, 131, 373-375.
Sahai, H. and Khurshid, A. (1993b). “Confidence intervals for the ratio of two Poisson 
means”, MathScntst, 18, 43-50.
D'Agostino R. B., Vasan R. S., Pencina M. J., Wolf P. A., Cobain M., Massaro J. M., et al. . 
(2008). General cardiovascular risk profile for use in primary care. Circulation 117, 743–53.
 
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case
of the binomial. Biometrika, 26; 404–413.
Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease 
prevention in clinical practice: The Sixth Joint Task Force of the European Society of 
Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice 
(constituted by representatives of 10 societies and by invited experts) Developed with the 
special contribution of the European Association for Cardiovascular Prevention & 
Rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315–2381. doi:10.1093/eurheartj/ehw106
Liu, G.F., Wang, J., Liu, K. and Snavely, D.B. (2006), Confidence intervals for an exposure 
adjusted incidence rate difference with applications to clinical trials. Statist. Med., 25: 1275-
1286. doi:10.1002/sim.2335.
Samuel Cykert, Darren A DeWalt, Bryan J Weiner, Michael Pignone, Jason Fine, Jung In 
Kim, A population approach using cholesterol imputation to identify adults with high 
cardiovascular risk: a report from AHRQ’s EvidenceNow initiative, Journal of the American 
Medical Informatics Association, Volume 26, Issue 2, February 2019, Pages 155–158, 
https://doi.org/10.1093/jamia/ocy151


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Appendix A
General principle on analysis sets and data 
selection in the virtual data warehouse
Any analysis based on the virtual data warehouse must make use of three mandatory data 
selection flags and a treatment option: only the combination of the three mandatory variables 
will allow a valid and meaningful data selection. The three mandatory flags are (1) the group 
flag, (2) the analysis set (3) the data selection flag. The following flags should be considered:

A group flag (study and timeframe selection, mandatory): The group flag will select 
all data (on an observation level) from patients in a predefined group of studies up to the 
cut-off date in pools that have a nominal cut-off date, and all data that are in scope of the 
respective pool in pools that have no nominal cut-off date. Group flags exist for F and G. 

Analysis Set flag (patient selection, mandatory): An analysis set (i.e. an analysis 
population) is defined as a subset of patients who fulfill certain inclusion criteria. The 
analysis set flag will select patients within a predefined pool of studies that fulfill the 
inclusion criteria of the respective population (e.g. SAF).

Data selection flag (observation selection, mandatory): The data selection flag will flag 
the relevant subset of observations to be included in an analysis from all the observations 
under consideration as defined by the group flag and the analysis set flag. The data 
selection criteria are uniquely defined by a combination of the pool definition (e.g. G), the 
analysis population (e.g. SAF), and the data domain (e.g. AE). 

Subgroup flag (patient level, optional): A subgroup flag is a flag that selects a subset of 
patients who share common (baseline) criteria from the overall analysis set. If no 
subgroup flag is selected all patients within the analysis set will be considered.

Visit (observation selection, optional): Used for analyses by visit, or for an analysis at a 
specific visit. If a remapped “VISIT” variable exists in a specific panel then this should be 
used.

A treatment option (mandatory): The treatment option will determine how patients are 
grouped in an analysis. This applies to statistical modeling and to the grouping of patients 
on outputs. For reports based on G this will usually be the initial cohort treatment option. 


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Rules for the derivation of “group flags” (Study and timeframe)
The group flag will select all observations from patients in a predefined group of studies from 
the baseline record up to the cut-off date in pools that have a nominal cut-off date, and all data 
that are in scope of the respective pool in pools that have no nominal cut-off date. For 
PASSAGE, only Group G and Group F flags will be used, and they will select all 
observations in PASSAGE. Unless otherwise specified, the mandatory flags used for 
PASSAGE analyses are summarized in table below:
Table A-1
Mandatory flags in PASSAGE main analysis
PASSAGE 
Analysis
Group flag
(GRPFLG)
Analysis set 
flag
Data 
selection flag
Treatment 
option
Group G 
Effectiveness analyses
G
To be derived 
by 
To be derived 
by 
TRTN_RI
Safety analyses 
(based on Group G
general safety rules)
G
SAF_G
FLGSAFCO
TRTN_CO
Group F
Safety analyses
(based on Group F 
general safety rules)
F
SAF_EF
FLGSAF_F
All patients in 
Group F


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Appendix B
Illustration of VDW key dates 
In Group G, dates of interest are:

FIRSMD1O, defined as the date of first dose of initial cohort treatment in the study (Day 1 
date)

FIRSMD9O, defined as the date of first dose of DMT in the study after the first permanent 
switch.

LSTSMD8O, defined as the date of last dose of initial cohort treatment prior to first 
permanent switch.

LSTDMT1, derived by 
and defined as the date of last dose of first DMT 
corresponding to cohort assignment prior to any switch in DMT and prior to an 
interruption in the first DMT corresponding to cohort assignment of more than 45 days. 
In Group F, dates of interest are:

FIRSMD3O, defined as the first dose of FTY720 during the study.

LSTSMD3O, defined as the date of last dose of FTY720 in the study.


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Appendix C
Sample Illustration of Prior MS DMT and Initial 
cohort treatment ongoing at study entry duration 
calculations


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Appendix D
Criteria for notable laboratory abnormalities
Table D-1
Criteria for notable laboratory abnormalities
Notable Values
Laboratory Variable
Standard Units
SI Units
HEMATOLOGY VARIABLES
WBCs (Leukocytes)
2.0 k/mm3
15 k/mm3
2.0 x 109/L
15 x 109/L
HEMATOLOGY VARIABLES: DIFFERENTIAL
Absolute lymphocytes
<200/mm3
8000/mm3
<0.2 x 109/L
8 x 109/L
Notable Values
Laboratory Variable
Criterion
LIVER FUNCTION AND RELATED VARIABLES
SGOT (AST) or AGPT (ALT)
>3-<=5 x ULN
>5-<=8 x ULN
>8-<=10 x ULN
>10-<=20 x ULN
>20 x ULN
Total bilirubin (TBL)
>1-<=1.5 x ULN
>1.5-<=2 x ULN,
>2 x ULN
Alkaline Phosphatase  (ALP)
>1.5-<=2 x ULN
>2-<=5 x ULN
>5 x ULN
COMBINED CRITERIA
ALP and TBL
ALP>3 x ULN and TBL>2 x ULN
ALP>5 x ULN and TBL>2 x ULN
AST or ALT and TBL
AST or ALT >3 x ULN and TBL >1.5 x ULN
AST or ALT >3 x ULN and TBL >2 x ULN
AST or ALT and TBL and ALP
AST or ALT >3 x ULN and TBL >2 x ULN and ALP <2 x ULN (Hy's 
Law)
ULN = Upper Limit of Normal


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Appendix E
Notable vital signs criteria
Table E-1
Notable vital signs criteria
NOTABLE VITAL SIGNS
Vital Sign Variable
Notable Criteria
Pulse (beats/min)
>120 bpm or Increase of 15 bpm 
Or
< 50 bpm or Decrease of 15 bpm 
Systolic BP (mmHg)
160 mmHg  or Increase of 20 mmHg 
Or
90 mmHg  or Decrease of 20 mmHg 
Diastolic BP (mmHg)
100 mmHg or Increase of 15 mmHg 
Or
50 mmHg or Decrease of 15 mmHg 
Body Weight (kg)
7% increase or decrease
Note that for Group G, an increase or decrease refers to a change from the value prior to first 
dose of initial cohort treatment in study. For Group F, an increase or decrease refers to a 
change from the value prior to first dose of FTY720 in study.


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Appendix F
Mapping of MS medications to the 7 categories of 
1st DMT corresponding to cohort assignment
Table F-1
Mapping of MS medications
1st DMT categories
Original preferred term
FTY720
FINGOLIMOD
FINGOLIMOD HYDROCHLORIDE
INTERFERON
BETASERON
INTERFERON BETA
INTERFERON BETA-1A
INTERFERON BETA-1B
INTERFERON
PEGINTERFERON, PEGINTERFERON BETA-1A
GLATIRAMER ACETATE
GLATIRAMER 
GLATIRAMER ACETATE
DIMETHYL FUMARATE
DIMETHYL FUMARATE
ETHYL FUMARATE
FUMARIC ACID
FUMARATE DISODIUM
TERIFLUNOMIDE
TERIFLUNOMIDE
NATALIZUMAB
NATALIZUMAB
Other MS therapies
All other DMTs 
Note: First DMTs corresponding to initial cohort treatment within the "Other MS therapies" category will be 
displayed as separate category if there are 40 or more patients with this DMT. 


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Appendix G
Framingham risk score calculation
Table G-1
CVD points for women
Table G-2
CVD points for men


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Table G-3
CVD risk for women


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Table G-3
CVD risk for men


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Appendix H
Concomitant medications treating sBP
Table H-1
ATC codes to identify CMs to treat sBP
ATC code
Name
C02
Antihypertensiva
C03
Diuretika
C07
Beta Blocker
C08
Calcium Antagonisten
C09
ACE Hemmer / Angiotensinantagonisten


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Appendix I
Cardiovascular risk factors 
Table I-1
Preferred terms for cardiovascular risk factors
Preferred term
Category
ALCHOL ABUSE                                                   
                       
ALCHOL USE                                   
                       
ALCOHOLISM                                   
                       
ANGINA PECTORIS                              
Cardiovascular disease 
ANGIOPLASTY                                  
Cardiovascular disease 
ANTIPHOSPHOLIPID ANTIBODIES                  
                       
ARTERIAL OCCLUSIVE DISEASE                   
                       
ARTERIAL THROMBOSIS                          
                       
ARTERIOSCLEROSIS                             
Cardiovascular disease 
ARTERIOSCLEROSIS CORONARY ARTERY             
Cardiovascular disease 
ATRIAL FIBRILLATION                          
                       
BLOOD CHOLESTEROL ABNORMAL                   
Hyperlipidaemia        
BLOOD CHOLESTEROL INCREASED                  
Hyperlipidaemia        
BLOOD GLUCOSE INCREASED                      
Diabetes mellitus      
BLOOD PRESSURE DIASTOLIC INCREASED           
Hypertension           
BLOOD PRESSURE INCREASED                     
Hypertension           
BLOOD TRIGLYCERIDES INCREASED                
Hyperlipidaemia        
BODY FAT DISORDER                            
                       
BODY MASS INDEX INCREASED                    
                       
BRAIN STEM HAEMORRHAGE                       
Cardiovascular disease 
BRAIN STEM HAEMORRHAGE                       
Cardiovascular disease 
BRAIN STEM ISCHAEMIA                         
Cardiovascular disease 
CARDIAC ANEURYSM                             
                       
CARDIAC ARREST                               
Cardiovascular disease 
CARDIAC DISORDER                             
Cardiovascular disease 
CARDIAC FAILURE CHRONIC                      
Cardiovascular disease 
CARDIAC FAILURE CONGESTIVE                   
Cardiovascular disease 
CARDIOLIPIN ANTIBODY POSITIVE                
                       
CARDIOMEGALY                                 
Cardiovascular disease 
CARDIOMYOPATHY                               
Cardiovascular disease 
CARDIOVASCULAR DISORDER                      
Cardiovascular disease 
CAROTID ARTERY DISEASE                       
Cardiovascular disease 
CAROTID ARTERY STENOSIS                      
Cardiovascular disease 
CAROTID ARTEY STENT INSERTION                
                       
CEREBROVASCULAR ACCIDENT                     
Cardiovascular disease 
CEREBROVASCULAR DISORDER                     
Cardiovascular disease 
CEREBROVASCULAR INSUFFICIENCY                
Cardiovascular disease 
CIRCULATORY COLLAPSE                         
                       
COAGULOPATHY                                 
                       
CORONARY ANGIOPLASTY                         
Cardiovascular disease 
CORONARY ARTERIAL STENT INSERTION            
Cardiovascular disease 


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CORONARY ARTERY BY-PASS                      
                       
CORONARY ARTERY DISEASE                      
Cardiovascular disease 
DEEP VEIN THROMBOSIS                         
                       
DIABETES MELLITUS                            
Diabetes mellitus      
DIABETIC DIET                                
Diabetes mellitus      
DIABETIC HYPEROSMOLAR COMA                   
Diabetes mellitus      
DIABETIC KETOACIDOSIS                        
Diabetes mellitus      
DIABETIC METABOLIC DECOMPENSATION            Diabetes mellitus      
DIABETIC NEUROPATHY                          
Diabetes mellitus      
DIASTOLIC DYSFUNCTION                        
Cardiovascular disease 
DIASTOLIC HYPERTENSION                       
Hypertension           
DYSLIPIDAEMIA                                
Hyperlipidaemia        
EMBOLISM VENOUS                              
                       
ESSENTIAL HYPERTENSION                       
Hypertension           
EX-ALCHOLIC                                  
                       
EX-TOBACCO USER                              
                       
FACTOR V LEIDEN MUTATION                     
                       
HAEMORRHAGIC STROKE                          
Cardiovascular disease 
HIGH DENSITY LIPOPROTEIN DECREASED           
Hyperlipidaemia        
HYPERCHOLESTEROLAEMIA                        
Hyperlipidaemia        
HYPERLIPIDAEMIA                              
Hyperlipidaemia        
HYPERTENSION                                 
Hypertension           
HYPERTENSIVE CRISIS                          
Hypertension           
HYPERTRIGLYCERIDAEMIA                        
Hyperlipidaemia        
HYPERTROPHIC CARDIOMYOPATHY                  
Cardiovascular disease 
INSULIN REQUIRING TYPE 2 DIABETES 
MELLITUS   
                       
ISCHAEMIC CARDIOMYOPATHY                     
Cardiovascular disease 
JUGULAR VEIN THROMBOSIS                      
                       
LABILE HYPERTENSION                          
Hypertension           
LEFT VENTRICULAR HYPERTROPHY                 
Cardiovascular disease 
LIPID METABOLISM DISORDER                    
Hyperlipidaemia        
LIPIDS INCREASED                             
Hyperlipidaemia        
LOW DENCITY LIPOPROTEIN INCREASED            
                       
METABOLIC SYNDROME                           
                       
MYOCARDIAL INFARCTION                        
Cardiovascular disease 
MYOCARDIAL ISCHAEMIA                         
Cardiovascular disease 
NICOTINE DEPENDENCE                          
                       
OBESITY                                      
                       
OVERWEIGHT                                   
                       
PRE-ECLAMPSIA                                
                       
PRINZMETAL ANGINA                            
Cardiovascular disease 
PROTEIN S DEFICIENCY                         
                       
SYSTOLIC HYPERTENSION                        
Hypertension           
THROMBOSIS                                   
                       
TOBACCO ABUSE                                
                       
TOBACCO USER                                 
                       


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TRIANSIENT ISCHAEMIC ATTACK                  
                       
TYPE 1 DIABETES MELLITUS                     
Diabetes mellitus      
TYPE 2 DIABETES MELLITUS                     
Diabetes mellitus      
TYPE IIA HYPERLIPIDAEMIA                     
Hyperlipidaemia        
TYPE V HYPERLIPIDAEMIA                       
Hyperlipidaemia        
VENOUS THROMBOSIS                            
VENOUS THROMBOSIS LIMB                       
WEIGHT INCREASED                             
Aortic valve disease    
Cardiovascular disease 
Pulmonary valve incompetence     
Cardiovascular disease 
Left ventricular dysfunction   
Cardiovascular disease 
Heart valve incompetence
Cardiovascular disease 
Cardiac valve disease   
Cardiovascular disease 
Cardiomegaly   
Cardiovascular disease 
Aortic valve incompetence             
Cardiovascular disease 
Ischaemic cardiomyopathy     
Cardiovascular disease 
Mitral valve incompetence             
Cardiovascular disease 
Mitral valve disease                  
Cardiovascular disease 
Overweight
Cardiovascular disease 
Carotid artery aneurysm                      
Cardiovascular disease
Carotid artery dissection  
Cardiovascular disease 
Carotid artery occlusion  
Cardiovascular disease 
Cerebral arteriosclerosis 
Cardiovascular disease 
Congenital mitral valve stenosis      
Cardiovascular disease 
Cardiac septal defect                 
Cardiovascular disease 
Congenital heart valve disorder       
Cardiovascular disease 
Electrocardiogram PR prolongation      
Cardiovascular disease 
Antiphospholipid antibodies  
Cardiovascular disease 
Antiphospholipid antibodies positive
Cardiovascular disease 
Electrocardiogram QRS complex prolonged
Cardiovascular disease 
Echocardiogram abnormal               
Cardiovascular disease 
Cardiolipin antibody
Cardiovascular disease 
Blood pressure increased    
Cardiovascular disease 
Electrocardiogram QT prolonged        
Cardiovascular disease 
Arterial occlusive disease            
Cardiovascular disease 
Pelvic venous thrombosis          
Cardiovascular disease 
Peripheral artery occlusion  
Cardiovascular disease 
Peripheral artery thrombosis          
Cardiovascular disease 
Aortic arteriosclerosis
Cardiovascular disease 
Venous stenosis                       
Cardiovascular disease 
Peripheral arterial occlusive  disease
Cardiovascular disease 
Intermittent claudication             
Cardiovascular disease 
Cardiac assistance device user        
Cardiovascular disease 
Aortic valve replacement 
Cardiovascular disease 
Peripheral artery angioplasty         
Cardiovascular disease 
Arterial stent insertion              
Cardiovascular disease 
Aortic valve repair
Cardiovascular disease 


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Cardiac operation  
Cardiovascular disease 
Cardiac septal defect repair            
Cardiovascular disease 
Impaired fasting glucose   
Diabetes mellitus      
Diabetic ketoacidosis  
Diabetes mellitus      
Diabetic metabolic decompensation 
Diabetes mellitus      
Insulin-requiring type 2 diabetes  mellitus
Diabetes mellitus      
Monogenic diabetes                    
Diabetes mellitus      
Hyperglycaemia
Diabetes mellitus      
Steroid diabetes                      
Diabetes mellitus      
Blood glucose increased               
Diabetes mellitus      
Blood pressure diastolic increased    
Hypertension     
         
Blood triglycerides increased     
Hyperlipidaemia    
Lipids 
Hyperlipidaemia    
Endocrine hypertension                
Hypertension


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Appendix J
Risk charts for European CVD risk score 
Table J-1
SCORE – European High Risk Chart


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Table J-2
SCORE – European Low Risk Chart


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Appendix K
Serious cardiovascular event definition
Table K-1
List of SMQs, HLTs and PTs defining a cardiovascular event
Term category
Coded Term*
SMQ (narrow)
Ischaemic heart disease (SMQ)                                    
SMQ (narrow)
Cardiac failure (SMQ)                                                   
SMQ (narrow)
Ischaemic central nervous system vascular 
conditions (SMQ)                          
SMQ (narrow)
Haemorrhagic central nervous system vascular 
conditions (SMQ)                       
SMQ (narrow)
Shock-associated circulatory or cardiac conditions 
(excl torsade de pointes) (SMQ)  
HLT
Accelerated and malignant hypertension
HLT
Ventricular arrhythmias and cardiac arrest
PT
Atrioventricular block complete
Additionally all PTs from SOC=Cardiac Disorders that are flagged as leading to death.
* Events fulfilling the definition must be serious.