Phase II Cladribine Add-on to Interferon-beta (IFN-b) Therapy in MS Subjects With Active Disease (ONWARD)

Inclusion Criteria:

• Be male or female, 18-65 years of age (inclusive);
• Weigh between 40-120 kg, inclusive;
• Have definite MS, as confirmed by the revised McDonald criteria (Polman, et al. 2005), and have relapsing forms of MS, such as relapsing-remitting or secondary progressive type of disease with superimposed relapses forms (See Appendix I);
• Have experienced at least one relapse while receiving IFN-b treatments (Rebif® 44 mcg tiw, sc; AvonexÒ 30 mcg qw, im; or BetaseronÒ 250 mcg qod, sc) for at least 48 weeks (prior to Screening);
• Minimum aggregate time on IFN-b therapy is 48-consecutive weeks prior to Screening. Subjects who switched from one IFN-b therapy to another in the 48 weeks preceding Screening may be entered into the study if they have been on a stable regimen of their current IFN-b therapy for a minimum of 3 months prior to Screening.
• Be clinically stable (other than MS relapse) during the 28 days preceding Screening;

• The following hematological parameters must be normal (as defined below, inclusively) within 28 days of first dosing of blinded study medication at SD 1 (see also Section Error! Reference source not found. for further Hematological Testing and Entry Guidelines):

  • Hemoglobin = 11.6 - 16.2 G/DL
  • Leukocytes (total white blood cells [WBC]) = 4.1 - 12.3 x10E3/UL
  • Absolute lymphocytes = = 1.02 - 3.36 x10E3/UL
  • Absolute neutrophil count (ANC) = 2.03 - 8.36 x10E3/UL
  • Platelet count = 140 - 450 x10E3/UL
• Have no medical history or evidence of latent tuberculosis infection (LTBI) or active tubercular disease (TB), as evidenced by TB skin test or chest X-ray (see Appendices O, P);
• Have an EDSS from 1.0-5.5, inclusive (See Appendix D);
• Have no prior exposure to immunosuppressive or cytotoxic agents (with the exception of steroids for MS flare management, or intravenous immunoglobulin-G [IVIG] after allowed wash-out periods.

Exclusion Criteria:

• Have primary progressive MS or secondary progressive MS without relapses forms;
• Have prior or current malignancy other than medically documented complete excision of basal cell skin cancer no less than 5 years prior to Screening;
• Have a history of chronic or clinically significant hematological abnormalities;
• Prior use of cladribine, mitoxantrone, campath-1h, cyclophosphamide, azathioprine, methotrexate, daclizumab, natalizumab, lymphoid irradiation, bone marrow transplantation or myelosuppressive/cytotoxic therapy;
• Use of cytokine or anti-cytokine therapy or plasmapheresis within 3 months prior to Study Day 1;
• Treatment with intravenous immunoglobulin-G (IVIG) within 30 days of Screening;
• Treatment with oral or parenteral corticosteroids within 2 weeks of Screening;
• Treatment with adrenocorticotropic hormone within 28 days prior to Study Day 1;
• Use of any investigational drug (other than Rebif® New Formulation [RNF]) or experimental procedure within 6 months prior to Study Day 1;
• Subject has inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase > 2.5 times the upper limit of the normal values;
• Subject suffers from major medical illness such as cardiac, endocrinologic, hepatic, immunologic (other than MS), metabolic, renal, pulmonary, gastrointestinal, dermatologic, or other major disease that would preclude the administration of oral cladribine.
• Subject suffers from major psychiatric illness (including history of, or current, severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol;
• History of active or chronic infectious disease or any disease which compromises immune function (e.g. HIV+, HTLV-1, Lyme disease, LTBI or TB);
• Have an allergy or hypersensitivity to gadolinium, to cladribine or any of its excipients, or IFN-b or any of its excipient(s);
• Have any renal condition that would preclude the administration of gadolinium (e.g. acute or chronic severe renal insufficiency (GFR < 30mL/min/1.73m2);
• Have a positive stool heme-occult test at Screening (see also Section Error! Reference source not found. for further Heme-Occult Testing and Entry Guidelines);
• Subject has a history of seizures not adequately controlled by treatment.