The primary objective of this study is to explore the effects of multiple regimens of natalizumab on disease activity and safety in participants with relapsing-remitting Multiple Sclerosis (RRMS).

This is a a dose and frequency (but not route of administration) blinded, prospective, randomized, dose-ranging study in patients with RRMS who have received natalizumab for at least 12 months according to the local prescribing guidelines. The study will explore dosing of natalizumab by subcutaneous and intravenous routes. Participants will be randomly assigned to 1 of 6 dosing regimens, blinded to natalizumab dose, but not route, for 60 weeks of treatment.

Key Inclusion Criteria:

• Ability to provide written informed consent
• Subjects of childbearing potential must practice effective contraception during the study
• A documented diagnosis of Relapsing Remitting Multiple Sclerosis (RRMS)
• Free of MS relapse for 12 months prior to randomization
• Treatment with natalizumab for a minimum of 12 months immediately prior to randomization.
• In the 12 months prior to commencing natalizumab, subject must have experienced a minimal level of disease activity as defined by 2 or more documented clinical relapses OR 1 relapse and documented MRI activity, defined by the presence of at least 1 Gd enhancing lesion on MRI, unrelated to the relapse.

Key Exclusion Criteria:

• Known history of Human Immunodeficiency Virus (HIV), hepatitis C and/or hepatitis B virus
• Positive for anti-natalizumab antibodies at screening
• MRI positive for Gd-enhancing lesions at study entry
• Subjects for whom MRI is contraindicated
• History of any clinically significant cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic (including diabetes), urologic, pulmonary, neurologic (except for RRMS), dermatologic, psychiatric, renal, or other major disease
• History of malignant disease, including solid tumors and hematologic malignancies (with the exception of cured basal cell and squamous cell carcinomas of the skin)
• History of transplantation or any anti-rejection therapy
• History of severe allergic or anaphylactic reactions or known hypersensitivity to any drug
• A clinically significant infectious illness within 30 days prior to screening or progressive multifocal leukoencephalopathy (PML) or other opportunistic infections at any time
• Signs or symptoms suggestive of any serious infection, based on medical history, physical examination or laboratory testing

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.