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.