Effects of Gilenya (Fingolimod) on Thalamus Pathology and Cognitive Impairment in Patients With Relapsing Forms of Multiple Sclerosis

This is an open-label, single-blinded, observational, prospective, 24 months follow-up,
controlled study to assess the efficacy of Gilenya on thalamus pathology and cognitive
impairment in 30 relapsing MS patients naïve to Gilenya who fulfilled the inclusion and
exclusion criteria used for screening and started Gilenya, on a clinical basis. In addition,
20 HCs will be included as a reference population. Because this is an observational study
investigating evolution of thalamic atrophy, iron deposition, cognitive dysfunction and
response to herpes viruses in patients treated with Gilenya on a clinical basis the patients
are not starting Gilenya as an investigational drug. Therefore, the patients who are already
started Gilenya by the treatment decision of their physician will be asked to participate in
this observational study.

The screening and starting procedures criteria for Gilenya on a clinical basis and for our
study are defined by the Gilenya PI. All patients in our clinic have standardized assessments
before starting any disease-modifying therapy. Once the patient decided to start Gielnya on a
clinical basis and qualified on a screening, as defined by Gilenya PI, our team will be
informed and contact the patient regarding participation in the present study before
receiving first dose of Gilenya. Once the informed consent is signed, the patient will follow
study procedures, as outlined in the protocol and study evaluation schedule. All subjects
will be assessed at 0, 6, 12 and 24 months with the same clinical, 3T MRI and laboratory, and
humoral response to herpes viruses examinations. The cognitive assessments and evaluation of
environmental risk factors will be performed at 0, 12 and 24 months. Safety will be also
assessed at 0, 6, 12 and 24 months of the study.

The healthy controls (HC) will serve as reference comparison group to patients for atrophy
iron, cognitive and response to herpesvirus outcomes. We considered alternative study designs
as listed below. The head-to-head comparison with untreated or comparator-treated patients
are difficult to conduct and can not be performed without proper randomization and
double-blinding which is costly and unfeasible in mechanistical study like is the one
proposed. The inclusion of a HC group provides a valuable baseline, allowing evaluation of
the proposed techniques for normal variation between individuals, against which changes in
the proposed outcomes could be compared. Use of HCs for comparison with a patient population
in prospective longitudinal pilot studies of non-conventional MRI, including measurement of
thalamic atrophy and iron deposition, may become an attractive approach in the future for
several reasons. First, the ultimate goal of therapy is to normalize patient changes over
time, to those observed in HCs over the same time period. HCs also experience brain changes
over time and so the notion of arresting disease progression as measured by proposed outcomes
requires validation by reference to a comparator without disease progression to account for
age-related changes. Second, ethical considerations preclude placebo-controlled studies using
an established MS treatment versus placebo-treatment in patients with RRMS.

The MRI analysis will be performed fully blinded, as are all phase I, II, III and IV trials
calculated at the Buffalo Neuroimaging Analysis Center (BNAC), Buffalo, NY. BNAC has been
involved as an centralized MRI reading center in many MS clinical trials that included over
500 sites around the world in 55 countries The detailed procedures of how the MRI DICOM files
are blinded and how the workload is distributed are part of our internal standard operating
procedures (SOPs) that have been accepted as appropriate following standard audits by
government and industry agencies.

All participants will undergo study eligibility screening and consenting by a Clinical
Research Project Coordinator. The participant will be provided with a description of the
required testing for study participation, and any risks will be described in order for the
person to make an informed decision regarding voluntary study participation. This is also an
opportunity for the person to ask questions regarding the study and the testing components.
All study participants who choose to enroll in the study will be asked to sign and date the
consent form in front of the Study Coordinator who will also sign and date the consent as
witness.

Inclusion Criteria:

- Patient diagnosed with MS according to McDonald criteria

- Age 18-60

- Have a relapsing disease course or a Healthy Control

- Have EDSS scores 0-6.5

- Have a disease duration <20 years

- Patients who have been clinically cleared and have agreed with their neurologist to
begin therapy with Gilenya will be asked to enroll in this prospective study. No drug
will be administered as part of this study.

- Be willing and able to comply with the study procedures for the duration of the trial

- Have given written informed consent and signed Health Insurance Portability and
Accountability Act (HIPAA) Authorization before any study-related activities are
carried out

- Normal kidney functioning (creatinine clearance >59) - patients only

- None of the exclusion criteria

Exclusion Criteria:

- Have received treatment within 30 days prior to enrollment with steroids or any other
concomitant immunomodulatory therapies (e.g., interferon-beta, glatiramer acetate,
intravenous immunoglobulin)

- Less than 6 months from the use immunosuppressant agents (e.g. including but not
limited to mitoxantrone, cyclophosphamide, azathioprine, methotrexate, CellCept,
natalizumab

- Ever use of cladribine, fludarabine, or total body irradiation) alemtuzumab/Campath

- Have received an investigational drug or experimental procedure within the past 30
days

- Women who are pregnant, lactating or of childbearing age who do not consent to
approved contraceptive use during the study

- Abnormal blood tests (pre-dose assessment as per site procedure for patients
considered for Gilenya treatment), including ALT or AST greater than two times the
upper limit of normal