Assessment of Tecfidera® in Radiologically Isolated Syndrome (RIS)

This is a multi-center, randomized, double-blinded study in which approximately 210 RIS
(radiologically isolated syndrome) subjects will be treated with either Tecfidera or placebo
for 2 years (1:1 randomization). Study participants, along with the treating and examining
physicians, will be blinded to treatment assignment. Central Clinical and Imaging Units will
screen all potential study subjects for inclusion/exclusion criteria. We expect to enroll all
RIS subjects within the U.S.

Following informed consent and verification of entry criteria by the core units, study
participants will be randomized 1:1 to either Tecfidera (120mg by mouth twice daily for 7
days with dose escalation to 240mg by mouth twice daily) or placebo. Clinical follow-up by
the treating physician will occur at weeks 0, 48, 96, 144 and/or End of Study and during or
immediately following clinical exacerbations. During clinical visits, comprehensive medical
history data will be obtained by the treating physician. All reported acute or progressive
clinical events will be adjudicated by the Central Clinical Unit. Clinical visits due to
suspected exacerbations associated with CNS (central nervous system) demyelination, and
associated diagnostic studies and treatments, will be covered under the medical standard of
care by third party payers. A recommendation to re-evaluate the patient within 3 months
following the clinical event to assess for extent of recovery will be made. In addition to
the face-to-face visits described above, study participants will be contacted over the
telephone at weeks 4, 8, 36, 60, 84, 108, and 132 to assess for medical or treatment
difficulties and for study medication compliance. Standardized MRI studies of the brain will
be performed at weeks 0, 96, 144 or End of Study. Clinical imaging studies of the brain
and/or spinal cord performed during or immediately following the onset of a clinical
exacerbation will be performed at the discretion of the site PI with scan costs covered under
the medical standard of care. An end of study clinical MRI of the cervical spinal cord with
and without contrast will be recommended to study participants at week 96 as medical standard
of care.

Inclusion criteria

1. Males and females meeting 2009 RIS criteria

2. Identified RIS cases with the initial MRI demonstrating anomalies suggestive of
demyelinating disease dated > 2009

3. Incidental anomalies identified on MRI of the brain or spinal cord with the primary
reason for the acquired MRI resulting from an evaluation of a process other than MS

4. CNS white matter anomalies meeting the following MRI criteria:

- Ovoid, well-circumscribed, and homogeneous foci with or without involvement of
the corpus callosum

- T2-hyperintensities measuring > 3mm2 and fulfilling 3 of 4 Barkhof-Tintoré
criteria for dissemination in space

- CNS anomalies not consistent with a vascular pattern

- Qualitative determination that CNS anomalies have a characteristic appearance of
demyelinating lesions

5. MRI anomalies do not account for clinically apparent neurological impairments in
patients

Exclusion criteria

1. Women who are pregnant or nursing

2. Incomplete medical history or radiological data

3. History of remitting clinical symptoms consistent with multiple sclerosis lasting > 24
hours prior to CNS imaging revealing anomalies suggestive of MS

4. History of paroxysmal symptoms associated with MS (i.e. Lhermitte's or Uhthoff's
phenomena)

5. CNS MRI anomalies are better accounted for by another disease process

6. The subject is unwilling or unable to comply with the requirements of the study
protocol

7. Exposure to a disease modifying therapy for MS/RIS within the past 3 months

8. Exposure to high-dose glucocorticosteroid treatment within the past 30 days

9. Participation in other clinical trials involving treatment with a disease-modifying
agent