Combination Therapy (Provigil + Avonex) to Treat Cognitive Problems in MS

MS has been associated with fatigue, attention problems, and a number of cognitive
difficulties. There is no treatment approved yet to treat these problems. Although certain
immunomodulatory treatments may slow the progression of cogntiive difficulties, they are not
therapy for the progression of or new onset of such problems. Therefore, in order to treat
such problems, it is likely that adjunctive medications focused on fatigue and cognition are
needed. We hypothesize that the addition of Provigil to an existing immunomodulatory agent
(Avonex) will lead to improved fatigue, attention, and overall cognition in MS patients with
attention problems.

Study Period: 6 to 12-month competitive enrollment period, two groups (Avonex and Avonex
+Provigil 200 mg QD ) undergo baseline (prior to starting Provigil), 2-month, and 4-month
neuropsychological evaluations. Total length of study, once initiated, (including 2 month
preparation period, 6 to 12-month competitive enrollment period through final four-month
visit) is 12 to 18 months.

Primary Objective: To investigate whether Provigil in combination with Avonex is safe, and
tolerable in patients with RRMS.

Secondary Objectives:

1. To determine whether Provigil (modafinil) in combination with Avonex(interferon β-1a)
is useful in treating deficits in attention, as measured by objective
neuropsychological tests, in patients with RR-MS

2. To determine whether combination therapy (Avonex +Provigil) favorably impacts other
domains of cognition that are reliant on attention (e.g., memory, psychomotor
functioning), as measured by objective neuropsychological tests, in patients with RR-MS

3. To determine whether improvement in fatigue (related to treatment) predicts
improvements in attention and cognitive performance in MS patients

Inclusion Criteria:

- Patients entering the study will:

- Be taking Avonex

- Have normal laboratory blood tests and EKG

- Be complaining of attention problems to treating neurologist

- Be English-speaking males and females between the ages of 25 and 60, inclusive
[If patient is female, she must

- Be surgically sterile; or

- Be 2 years postmenopausal; or

- If of child-bearing potential, must be using a medically accepted method of
birth control and agree to continue to use this method for the duration of
the study (i.e., barrier method with spermicide, steroidal contraceptive
[oral, implanted, and Depo-Provera contraceptives must be used in
conjunction with a barrier method], IUD, or abstinence)]

- Have clinically definite RR MS with disease duration of less than 10 years

- Have an EDSS score between 0 and 5.5

- Have corrected vision of no worse than 20/50

- Have between 10 and 20 years of education

- Be cerebral-stimulant free for at least one week prior to Attention Screening

- Be able to complete self-rating scales and cognitive assessment tools

- Have provided written informed consent

- To have performed at least one standard deviation below normative expectation on
at least two of four measures in the attention screening evaluation

Exclusion Criteria:

- Patients entering the study will NOT:

- A history of heart disease or liver dysfunction

- Have abnormal EKG or laboratory blood work,

- Have a history of psychosis

- Be a significant risk of suicide

- Be abusing alcohol (current and within last 2 years)

- Be abusing controlled substances (current and within last 2 years)

- Have any medical ailment which can produce fatigue, such as lupus, anemia or
thyroid disease

- Have any history of clinical deviation from normal ranges in the physical
examination

- Have an unstable medical disorder, or medical contraindication to the use of
Provigil

- Have any history of head injury, seizures, or neurological conditions involving
the central nervous system other than RR MS

- Have any disorder that may interfere with drug absorption, distribution,
metabolism, or excretion, including gastrointestinal surgery

- Be a pregnant or lactating female (any patient becoming pregnant during the
study will be discontinued)

- Have received any investigational product within 30 days of Cognitive Screening

- Have upper extremity dysfunction that prohibits them from using a computer mouse
writing with a pencil

- Be colorblind