Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study Two (CARE-MS II)

• Time to Sustained Accumulation of Disability (SAD) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Relapse Rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• Time to Sustained Accumulation of Disability (SAD) [ Time Frame: 2 years ]
• Relapse Rate [ Time Frame: 2 years ]

• Proportion of patients who are relapse free at Year 2 [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Change from baseline in EDSS (Expanded Disability Status Scale) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Acquisition of disability as measured by change from baseline in Multiple Sclerosis Functional Composite (MSFC) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Percent change from baseline in MRI-T2 hyperintense lesion volume at Year 2 [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• Proportion of patients who are relapse free at Year 2 [ Time Frame: 2 years ]
• Change from baseline in EDSS [ Time Frame: 2 years ]
• Acquisition of disability as measured by change from baseline in MSFC [ Time Frame: 2 years ]
• Percent change from baseline in MRI-T2 hyperintense lesion volume at Year 2 [ Time Frame: 2 years ]

The purpose of this study is to establish the efficacy and safety of two different doses of alemtuzumab as a treatment for relapsing-remitting multiple sclerosis (MS), in comparison with Rebif® (interferon beta-1a). The study will enroll patients who have received an adequate trial of disease-modifying therapies but continued to relapse while being treated, and who meet a minimum severity of disease as measured by magnetic resonance imaging (MRI). Patients will have monthly laboratory tests and comprehensive testing every 3 months.

Every patient will receive active treatment; there is no placebo. The 24 mg alemtuzumab dose is closed to enrollment so newly enrolled patients will be randomly assigned to treatment with either 12 mg alemtuzumab or Rebif® at a 2:1 ratio (ie, 2 given 12 mg or 24 mg alemtuzumab for every 1 given Rebif®). Alemtuzumab will be administered in two annual cycles, once at the beginning of the study and again 1 year later. Rebif® will be self-injected 3 times per week for 2 years. All patients will be required to return to their study site every 3 months for neurologic assessment. In addition, safety-related laboratory tests will be performed at least monthly. Participation in this study will end 2 years after the start of treatment for each patient. Additionally, patients who receive alemtuzumab may be followed in the CAMMS03409 Extension Study (NCT00930553) for safety and efficacy assessments. Patients who receive Rebif® and complete 2 years on study may be eligible to receive alemtuzumab in the Extension Study.

• Biological: alemtuzumab
  12 mg per day administered through IV, once a day for 5 consecutive days at Month 0 and 12 mg per day administered through IV, once a day for 3 consecutive days at Month 12
• Biological: alemtuzumab
  24 mg per day administered through IV, once a day for 5 consecutive days at Month 0 and 24 mg per day administered through IV, once a day for 3 consecutive days at Month 12 Note: The 24 mg alemtuzumab dose is closed to enrollment.
• Biological: interferon beta-1a (Rebif®)
  44 mcg administered 3-times weekly by SC injections for 2 years

• Experimental: alemtuzumab 12 mg
  Intervention: Biological: alemtuzumab
• Experimental: alemtuzumab 24mg
  Intervention: Biological: alemtuzumab
• Active Comparator: interferon beta-1a (Rebif ®)
  Intervention: Biological: interferon beta-1a (Rebif®)

• Fox E, Sullivan H, Gazda S. Open label, single-arm, Phase II study of alemtuzumab in patients with active relapsing-remitting multiple sclerosis who have failed licensed beta-interferon therapies. Poster presentation P06.07 at the 59th Annual Meeting of the American Academy of Neurology (AAN) on 03 May 2007.
• CAMMS223 Trial Investigators; Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK. Alemtuzumab vs. Interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008 Oct 23;359(17):1786-801.
• Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, Seaman S, Miller DH, Hale G, Waldmann H, Compston DA. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006 Jan;253(1):98-108. Epub 2005 Jul 27.
• Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Miller T, Fisher E, Sandbrink R, Lake SL, Margolin DH, Oyuela P, Panzara MA, Compston DA; CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24;380(9856):1829-39. doi: 10.1016/S0140-6736(12)61768-1. Epub 2012 Nov 1.

Inclusion Criteria:

• Diagnosis of MS and MRI scan demonstrating white matter lesions attributable to MS
• Onset of MS symptoms within 10 years
• EDSS score 0.0 to 5.0
• ≥2 MS attacks within 24 months, with ≥1 attack within 12 months
• ≥1 MS attack (relapse)during treatment with a beta interferon therapy or glatiramer acetate after having been on that therapy for at least 6 months within 10 years

Exclusion Criteria:

• Previous treatment with alemtuzumab
• Previous treatment with any investigational drug (i.e. a medication that is not approved at any dose or for any indication)
• Treatment with natalizumab, methotrexate, azothioprine or cyclosporine in the past 6 months
• Previous treatment with mitoxantrone, cyclophosphamide, cladribine, rituximab, or any other immunosuppressive, or cytotoxic therapy (other than steroid treatment)
• Any progressive form of MS
• Any disability acquired from trauma or another illness that could interfere with evaluation of disability due to MS
• Major systemic disease that cannot be treated or adequately controlled by therapy
• Active infection or high risk for infection
• Autoimmune disorder (other than MS)
• Impaired hepatic or renal function
• History of malignancy, except basal skin cell carcinoma
• Medical, psychiatric, cognitive, or other conditions that compromise the patient's ability to understand the patient information, to give informed consent, to comply with the trial protocol, or to complete the study
• Known bleeding disorder
• Of childbearing potential with a positive serum pregnancy test, pregnant, or lactating
• Current participation in another clinical study or previous participation in CAMMS323 (NCT00530348)
• Previous hypersensitivity reaction to any immunoglobulin product
• Known allergy or intolerance to interferon beta, human albumin, or mannitol
• Intolerance of pulsed corticosteroids, especially a history of steroid psychosis
• Inability to self-administer subcutaneous (SC) injections or receive SC injections from caregiver
• Inability to undergo MRI with gadolinium administration
• Unwilling to use a reliable and acceptable contraceptive method throughout the study period (fertile patients only)