A randomized, double-blind, clinical trial to assess the safety and efficacy of two doses of oral cladribine vs. placebo in subjects who had a first clinical demyelinating event (clinically isolated syndrome). Subjects in either the cladribine or placebo group may also enter treatment periods with open-label interferon-beta or open-label cladribine depending upon the disease status. The primary objective of this study is to evaluate the effect of 2 dosage regimens of oral cladribine vs. placebo on the time to conversion to Multiple Sclerosis (MS) (from randomization) according to the revised McDonald criteria in subjects with a first clinical demyelinating event at high risk of converting to MS.

This will be a randomized, double blind, three-arm, placebo-controlled, multi-centre trial to evaluate the safety and efficacy of oral cladribine versus placebo in the treatment of subjects who have sustained a first clinical demyelinating event within 75 days prior to the Screening. Subjects must have a minimum of 2 clinically silent lesions on the Screening MRI.

The study will include a pre-study evaluation period (Screening period: between 10 and 28 days prior to the start of treatment with blinded study medication (oral cladribine or placebo).

Depending upon the clinical course of their MS, subjects will then proceed from the Initial Treatment Period to either the Maintenance Treatment Period (with open-label interferon-beta treatment) or Long-Term Follow-up Treatment Period (with either open-label low-dose cladribine or no additional treatment (if no progression to MS has been noted after the initial treatment period). The single primary endpoint for the overall study, which will be determined during the Initial Treatment Period, is time to conversion to MS (from randomization), according to the revised McDonald criteria (2005).

For every subject, eligibility for study enrollment and entry into each of the study periods, and diagnosis of conversion to either McDonald MS or CDMS must be confirmed and approved by a Sponsor appointed study Adjudication Committee.

• Drug: Oral cladribine
  Low-dose oral cladribine - 1.75 mg/kg/year. Dosed once/week for 4 weeks at the start of a cycle.
• Drug: Oral cladribine
  Low-dose oral cladribine - 3.5 mg/kg/year. Dosed once/week for 4 weeks at the start of a cycle.
• Drug: Placebo
  Placebo will be administered to subjects. The placebo looks exactly like the active treatment.

• 1: Experimental
  Low-dose oral cladribine
  Intervention: Drug: Oral cladribine
• 2: Experimental
  High-dose oral cladribine
  Intervention: Drug: Oral cladribine
• 3: Placebo Comparator
  Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

1. Be male or female between 18 and 55 years old, inclusive (see Appendix C)
2. Must weigh between 40-120 kg, inclusive
3. Has experienced a single, first clinical event suggestive of MS within 75 days prior to the Screening visit, (clock starts 24 hours after onset). The event must be a new neurological abnormality present for at least 24 hours, either mono- or polysymptomatic, other than a paresthesia, vegetative or cerebral dysfunction
4. Has at least two clinically silent lesions on the T2-weighted MRI scan, at screening, with a size of at least 3 mm, at least one of which is ovoid or periventricular or infratentorial on screening MRI
5. Has EDSS 0 - 5.0 for at least one time point during the screening period before start of treatment with blinded study medication
6. Have no medical history or evidence of latent tuberculosis infection (LTBI) or active tubercular disease (TB), as evidenced by TB skin test and/or chest X-ray

7. 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 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

8. If female, she must:

   • be neither pregnant nor breast-feeding, nor attempting to conceive and
   • use a highly effective method of contraception throughout the entire duration of the study and for 90 days following completion of the last dose of study medication. A highly effective method of contraception is defined as those which result in a low failure rate (i.e. less than1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomized partner, or
   • be post-menopausal or surgically sterilized [Note: for Danish sites only, subjects should use a hormonal contraceptive or intra-uterine device for the duration of the trial]
9. If male, he must be willing to use contraception to avoid contributing to pregnancies throughout the entire duration of the study and for 90 days following the last dose of study medication
10. Be willing and able to comply with study procedures for the duration of the study Voluntarily provide written informed consent, including, for USA, subject authorization under Health Insurance Portability and Accountability Act (HIPAA) (see Appendix J), prior to any study-related procedure that is not part of normal medical care, and with the understanding that the subject may withdraw consent at any time without prejudice to their future medical care.

Exclusion Criteria:

1. Subject has a diagnosis of multiple sclerosis (per McDonald criteria, 2005)
2. Subject has any other disease that could better explain the subject's signs and symptoms
3. Subject has complete transverse myelitis or bilateral optic neuritis
4. Subject uses or has used any other approved MS disease modifying drug (DMD)
5. Subject has used any investigational drug (other than Rebif® New Formulation) or undergone an experimental procedure within 12 weeks prior to SD1 with the exclusion of MS drug
6. Subject received oral or systemic corticosteroids or ACTH within 30 days prior to SD1
7. Subject has abnormal total bilirubin, or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase
8. Subject suffers from current autoimmune disease
9. Subject suffers from 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
10. Subject suffers from major medical illness such as cardiac (e.g. angina, congestive heart failure or arrhythmia), endocrinologic, hepatic, immunologic, metabolic, renal, pulmonary, gastrointestinal, dermatologic, or other major disease that would preclude the administration of oral cladribine
11. Subject has a history of seizures
12. Subject has a known allergy to cladribine, IFN-beta, the excipient(s) of the study medications, or to gadolinium-DTPA
13. Has any renal condition that would preclude the administration of gadolinium (e.g. acute or chronic severe renal insufficiency (GFR < 30 mL/min/1.73m2)
14. Has a history of chronic or clinically significant hematological abnormalities
15. History of active or chronic infectious disease or any disease that compromises immune function (e.g. HIV+, HTLV-1, Lyme disease, LTBI or TB, insulin-dependent diabetes).
16. Subject has previously been screened in this study thus signed an informed consent and than withdrawn
17. Subject has received any immunomodulatory or immunosuppressive therapy) at any time prior to Screening, including, but not limited to, the following products: any interferon, glatiramer acetate (Copolymer I), cyclophosphamide, cyclosporine, methotrexate, linomide, azathioprine, mitoxantrone, teriflunomide, laquinimod, cladribine, total lymphoid irradiation, anti-lymphocyte monoclonal antibody treatment (e.g. natalizumab, alemtuzumab/Campath, anti-CD4), intravenous immunoglobuline G (IVIG), cytokines or anti-cytokine therapy
18. Subject has received experimental MS treatment
19. Subject has a history of alcohol or drug abuse
20. Subject has intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen
21. Inability to administer subcutaneous injections either by self or by caregiver
22. Has prior or current malignancy (with the exception of in situ basal or squamous cell skin cancer surgically removed without recurrence for at least five years) Have a positive stool heme-occult test at Screening