Comparison of Rituximab Induction Therapy Followed by Glatiramer Acetate

This is a double blind, active comparator; single-center study involving up to 90 subjects
with qualifying CIS or RMS. Subjects who are not screen-failures must be randomized within 60
days of signing the informed consent document. Subjects who are not randomized within these
60 days must be re-screened for enrollment into the study. Patients will be stratified based
on their diagnosis of CIS or RMS (Relapsing Remitting or Secondary Progressive) and then
randomly assigned at a 1:1 ratio to either rituximab induction followed by standard GA
therapy (R-GA arm), or placebo induction followed by standard GA therapy (GA arm). Subjects
will receive an intravenous (IV) infusion of 1000 mg of rituximab or placebo (normal saline)
on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On
study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously
daily.

Study visits include screening, baseline/randomization (day 1), day 15, day 28 and then
visits every 3 months for up to 2.5 years. A month is defined as 28 days. On study day 15,
patients will receive the second dose of either rituximab or placebo; on study day 28
patients will begin treatment with GA therapy. Study days 15 and 28 have an acceptable window
of +/- 4 days. Follow-up phone calls are conducted every month to assess adverse events and
relapses. All monthly phone calls and quarterly visits must occur with a +/- 7 day window.
Unscheduled office visits for the evaluation of symptoms suggestive of relapses will be
scheduled as needed and may be prompted by questions elicited during the monthly safety and
relapse assessment phone calls, or on the basis of a phone call initiated by the patient. In
either case, those handling the phone call will interview the patient according to the
questions described in the PDDS will be administered. If a subject reports new or worsening
symptoms or there is a one point change in the PDDS score, an unscheduled visit will be
necessary. The examining clinician will administer the Expanded Disability Status Scale
(EDSS) but will be blinded to the PDDS score and type of visit (unscheduled or scheduled).
The treating clinician will determine if the neurological change is considered a relapse
based on EDSS scores provided by the EDSS evaluator and clinical presentation, and will make
the decision whether or not corticosteroids should be administered for the treatment of a
relapse. In addition, patients whose EDSS scores change sufficiently to qualify for SAD at
either scheduled or unscheduled visits, will be asked to come in for an additional visit, 12
weeks later, to determine whether the change is sustained.

A sub-group of patients who provide informed consent will be enrolled in the Lumbar Puncture
procedure. The procedure will be performed at the beginning of the study and at the 6 month
visit. The objective will be to examine changes in CSF T and B cells and correlate them with
evidence of disease activity by relapse, new MRI lesions and/or SAD. This procedure is
optional for patients and will have no impact on the overall study. Patients who do decide to
participate will sign an Addendum for Optional Procedure Consent Form The primary endpoint
will be the number of disease-free patients, defined as patients without new lesions on brain
MRI using the combined unique lesion approach (CUL), without sustained change in EDSS score
over any 3-month period and without relapse. Once the last patient randomized has completed
the final study visit for year 1 of the study, the data will be locked and an analysis
performed on all data collected up to that point. An independent Data and Safety Monitoring
Board (DSMB) will meet at initiation of the study and every 6 months thereafter until the end
of the study. Members of the DSMB may unblind themselves at their discretion and the DSMB
will include a statistician not directly involved in this study. If induction therapy fails
to show superiority at any point, the study will be stopped.

Standardized brain MRIs with and without gadolinium contrast will be obtained at baseline,
and month 6, 12, 18 and 24 months (for those patients reaching this point prior to the last
enrolled patient reaching the 12 months follow-up visit) at UCD Anschutz Medical Campus. The
treating clinician will have access to the MRI and can discuss the results openly with
subjects. Standardized MRIs will be obtained and interpreted locally by a physician who will
be blinded to the subject treatment to record the endpoints described above.

Assessments will be performed according to the schedule of events in section 4.1. Blinded
examiners will be utilized for the EDSS, MSFC and low contrast visual acuity assessments. Lab
results for B cell CD19+ counts will be collected by a blinded study coordinator who will
have them reviewed on a monthly basis by a qualified member of the DSMB for safety
assessment. But the CD19 B cell counts will not be available to the treating clinician unless
needed for safety.

The treating clinician and the study coordinator will manage the clinical care and study
related procedures. Complete metabolic panel (CMP) and liver function tests (LFT) will be
obtained once a year as Standard of Care, or more often if deemed necessary by the treating
clinician. Complete blood counts (CBC) with differential and CD19+ labs will be collected at
Baseline, month 1 and every 3 months from baseline to monitor B cell recovery. The examining
clinicians and primary study coordinator will be blinded to the CD19 lab results.

Inclusion Criteria:

- 18 through 55 years of age

- Patients with CIS demonstrating one unifocal neurological event AND at least 2
T2-weighted brain lesions measuring a minimum of 6mm in diameter by MRI analysis; or a
definite diagnosis of RMS, as defined by the 2005 revised McDonald criteria(1, 2), and
have had at least one clinically defined relapse within the past year OR one GEL on an
MRI within the past year

- Women of child-bearing potential must agree to practice an acceptable method of birth
control

- No evidence of progressive multifocal leukoencephalopathy (PML) or primary central
nervous system (PCNS) lymphoma

- Neurologically stable with no evidence of relapse or corticosteroid treatment within
30 days prior to randomization

- Subject must be able and willing to give meaningful, written informed consent prior to
participation in the trial, in accordance with local regulatory requirements.

Exclusion Criteria:

- ≥ 15 GELs on baseline MRI

- Treatment with interferon β, natalizumab, or fingolimod within three months of
randomization

- Treatment with mitoxantrone, cyclophosphamide, or any other chemotherapeutic agent for
MS or malignancy within 12 months of randomization

- Attenuated live virus vaccination within 4 weeks of randomization

- Positive urine and serum pregnancy test at screening or baseline visit

- Any prior treatment with alemtuzumab or cladribine

- Unable to tolerate GA

- History of cardiac arrhythmias, angina or any other significant cardiac abnormalities

- History of clinically significant chronic disease of the immune system or a known
immunodeficiency syndrome (HIV) other than MS

- White Blood Cell count of less than 2.5*10^9/L or lymphocyte count below 0.4*10^9/L

- Positive for any evidence of past, or current, hepatitis B and/or C infection

- History or presence of malignancy (except basal cell carcinoma)

- Clinically significant alcohol or drug abuse within past two years

- Any medical, psychiatric or other condition that could result in a subject not being
able to give fully informed consent, or to comply with the protocol requirements

- Inability to undergo MRI scans or history of hypersensitivity to gadolinium-
diethylenetriamine penta-acetic acid (DTPA)

- Participation in any clinical study evaluating another investigational drug or therapy
within three months prior to randomization

- Any other condition that, in the Investigator's opinion, makes the subject unsuitable
for participation in the study