A Phase II Study Comparing Low- and High-Dose Alemtuzumab and High-Dose Rebif® in Patients With Early, Active Relapsing-Remitting Multiple Sclerosis

• Sustained Accumulation of Disability (SAD), Confirmed Through 6 Months [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• Relapse [ Time Frame: 3 years ] [ Designated as safety issue: No ]

• Proportion of Patients Who Are Relapse Free at 3 Years After Initial Treatment. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• Magnetic Resonance Imaging (MRI) T1 to Determine Rate of Cerebral Atrophy (Decrease in Cerebral Volume) as Seen on MRI Brain Scan at 3 Years After Initial Treatment [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• Change in MRI T2 Lesion Volume at 3 Years After Initial Treatment. [ Time Frame: 3 years ] [ Designated as safety issue: No ]

This is a Phase II, randomized, open-label, three-arm study comparing two different doses of alemtuzumab and Rebif® in patients with early, active relapsing-remitting Multiple Sclerosis (MS) who have not been previously treated with MS therapies other than steroids.

The aims of treatment for multiple sclerosis (MS) therapy are to prevent the progression of disease and accumulation of long-term disability. The hypothesis underlying this study is that aggressive treatment of inflammation in the brain early in the course of MS will protect the patient from disease progression and accumulating disability.

This protocol compares two different doses of alemtuzumab and Rebif® to evaluate the kind of side effects that patients experience and to evaluate wich drug is better at:

• Slowing the sustained accumulation of disability in patients with MS
• Reducing the frequency of relapses that patients with MS experience);
• Reducing the effects of MS on the brain, as assessed by magnetic resonance imaging (MRI)

Patients who receive alemtuzumab during the initial 36-month treatment period may be eligible for additional alemtuzumab retreatment on either a fixed or an as-needed schedule to evaluate:

• How long the effects of prior alemtuzumab treatment last;
• If additional treatments with alemtuzumab continue to reduce the effects of MS; and
• What kind of side effects patients experience once patients begin taking alemtuzumab again

• Biological: interferon beta-1a (Rebif®)
  44 mcg administered 3-times weekly by SC injections for 36 months.
• 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; optional re-treatment at Month 24 depending on investigator discretion and laboratory assessments.

  After initial 36-month treatment period, eligible consenting patients will receive re-treatment on either a fixed schedule (2 annual cycles of 12 mg per day for 3 consecutive days) or an as-needed schedule (up to 2 cycles at least 12 months apart of 12 mg per day for 3 consecutive days only upon MS relapse or new brain abnormalities on MRI)

• 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; optional re-treatment at Month 24 depending on investigator discretion and laboratory assessments.

  After the initial 36-month treatment period, eligible consenting patients will receive retreatment on either a fixed schedule (2 annual cycles of 12 mg per day for 3 consecutive days) or an as-needed schedule (up to 2 cycles at least 12 months apart of 12 mg per day for 3 consecutive days only upon MS relapse or new brain abnormalities on MRI)

• Active Comparator: 1
  Intervention: Biological: interferon beta-1a (Rebif®)
• Experimental: 2
  Intervention: Biological: alemtuzumab
• Experimental: 3
  Intervention: Biological: alemtuzumab

• 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.
• Cuker A, Coles AJ, Sullivan H, Fox E, Goldberg M, Oyuela P, Purvis A, Beardsley DS, Margolin DH. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood. 2011 Dec 8;118(24):6299-305. Epub 2011 Sep 29.
• Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Bass AD, Wynn DR, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011 Apr;10(4):338-48.

Inclusion Criteria:

• Signed informed consent form.
• Male or non-pregnant, non-lactating female patients, 18 to 50 years of age (inclusive).
• Diagnosis of MS per McDonald's update of the Poser criteria, including cranial MRI consistent with those criteria.
• Onset of first MS symptoms within 3 years prior to screening.
• EDSS score 0.0 to 3.0 (inclusive) at the screening and baseline visits.
• At least 2 completed clinical episodes of MS in the 2 years prior to study entry (ie, the initial event if within 2 years of study entry plus ≥1 relapse, or ≥2 relapses if the initial event was between 2 and 3 years prior to study entry).
• In addition to the clinical criteria (3 to 6 above), ≥1 enhancing lesion on any 1 of the up to 4 screening gadolinium-enhanced MRI scans during a maximum 3-month run-in period (inclusive of the Month 0 baseline scan).

Exclusion Criteria:

• Previous immunotherapy for MS other than steroids, including treatment with interferons, intravenous immunoglobulin, glatiramer acetate, and mitoxantrone.
• Personal history of thyroid autoimmune disease.
• Personal history of clinically significant autoimmune disease (eg, inflammatory bowel disease, diabetes, lupus, severe asthma).
• History of thyroid carcinoma (previous thyroid adenoma is acceptable and is not to be considered an exclusion criterion).
• History of malignancy (except for basal cell skin carcinoma in which situation the patient is eligible only if disease-free for more or equal to 5 years).
• Any disability acquired from trauma or another illness that, in the opinion of the investigator, could interfere with evaluation of disability due to MS.
• Previous treatment with CAMPATH.
• History of anaphylaxis following exposure to humanized monoclonal antibodies.
• Inability to undergo MRI with gadolinium administration.
• Female patients with childbearing potential with a positive serum pregnancy test at screening or baseline. (NB: Serum pregnancy testing will be performed on each occasion.).
• Male and female patients who do not agree to use effective contraceptive method(s) during the study.
• Impaired renal function (ie, serum creatinine larger or equal to 2 times the Institutional upper limit of normal [ULN]).
• Untreated, major depressive disorder (MDD).
• Epileptic seizures that are not adequately controlled by treatment.
• Suicidal ideation.
• Major systemic disease or other illness that would, in the opinion of the investigator, compromise patient safety or interfere with the interpretation of study results.
• Abnormal CD4 count or significantly abnormal thyroid function; presence of anti-TSH receptor antibodies; known seropositivity for HIV.
• Intolerance of pulsed corticosteroids, especially a history of steroid psychosis.
• Presence of a monoclonal paraprotein.
• Patients who, in the opinion of the investigator, have any form of MS other than relapsing-remitting
• Patients currently participating in a clinical trial of an experimental or unapproved/unlicensed therapy