Oral Cladribine in Early Multiple Sclerosis (MS)
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Intervention: Cladribine; Placebo; Rebif® new formulation (RNF)
Intervention description: Cladribine tablets were administered until CDMS conversion, whichever occur first.; Placebo matched to cladribine tablets were administered.; Participants who converted to CDMS during ITP entered in open-label maintenance period (OLMP) and received RNF subcutaneously at a dose of 44 microgram (mcg) three times a week. Participants who converted to CDMS during long-term follow-up (LTFU) period, received RNF subcutaneously at a dose of 44 mcg three times a week.
Intervention MeSH terms: Cladribine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 617.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: Clinically Isolated Syndrome (CIS); Early MS; Multiple Sclerosis

Summary:

      A randomized, double-blind, clinical trial to assess the safety and efficacy of two doses of
      oral cladribine versus placebo in participants who had a first clinical demyelinating event
      (clinically isolated syndrome). Participants 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 two dosage regimens of oral cladribine versus placebo on the time to conversion to
      multiple sclerosis (MS) (from randomization) according to the Poser criteria in participants
      with first clinical demyelinating event at high risk of converting to MS.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female between 18 and 55 years old, inclusive

          -  Weighed between 40 to 120 kilogram (kg), inclusive

          -  Participant 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

          -  Participant has at least two clinically silent lesions on the T2-weighted MRI scan, at
             screening, with a size of at least 3 millimeter (mm), at least one of which is ovoid
             or periventricular or infratentorial on screening MRI

          -  Participant has EDSS 0 - 5.0 at Screening

          -  Participant has no medical history or evidence of latent tuberculosis infection (LTBI)
             or active tubercular disease, as evidenced by the Mantoux tuberculosis (TB) skin test
             or a comparable sensitive test according to local regulations/guidelines (if the
             Mantoux test is not available), and/or a chest X-ray

          -  Participant has normal hematological parameters at Screening, as defined by the
             central laboratory that performed all the assessments

          -  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 (that is less than 1 percent per year) when used
                  consistently and correctly such as implants, injectables, combined oral
                  contraceptives, some intrauterine devices, sexual abstinence or vasectomized
                  partner, or

               -  be post-menopausal or surgically sterilized (Note: for Danish sites only,
                  participants should use a hormonal contraceptive or intrauterine device for the
                  duration of the trial)

          -  Male participants must be willing to use contraception to avoid impregnating partners
             throughout the study, and for 90 days following the last dose of study medication

          -  Be willing and able to comply with study procedures for the duration of the study

          -  Participant has to provide written informed consent voluntarily, including, for United
             states of America (USA), participant authorization under Health Insurance Portability
             and Accountability Act (HIPAA), prior to any study-related procedure that is not part
             of normal medical care

          -  Participant has refused any treatment already available for clinically isolated
             syndrome (CIS) such as interferons or glatiramer acetate, at the time of entry into
             the Initial Treatment Period of this study

        Exclusion Criteria:

          -  Participant has a diagnosis of MS (per McDonald criteria, 2005)

          -  Participant has any other disease that could better explain the participant's signs
             and symptoms

          -  Participant has complete transverse myelitis or bilateral optic neuritis

          -  Participant using or has used any other approved MS disease modifying drug (DMD)

          -  Participant has used any investigational drug or undergone an experimental procedure
             within 12 weeks prior to Study day 1

          -  Participant received oral or systemic corticosteroids or adrenocorticotropic hormone
             (ACTH) within 30 days prior to screening MRI. The MRI had to be performed 30 days
             after the oral or systemic corticosteroids or ACTH treatment. In case this interfered
             with MRI timing the screening period could be extended accordingly.

          -  Participant has abnormal total bilirubin, or aspartate aminotransferase (AST) or
             alanine aminotransferase (ALT) or alkaline phosphatase greater than 2.5 times the
             upper limit of normal

          -  Participant suffered from current autoimmune disease other than MS

          -  Participant suffered from psychiatric illness (including history of, or concurrent,
             severe depressive disorders and/or suicidal ideation) that in the opinion of the
             investigator creates undue risk to the participant or could affect compliance with the
             study protocol

          -  Participant suffered from major medical illness such as cardiac (for example 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

          -  Participant has a history of seizures not adequately controlled by medications

          -  Participant has a known allergy to cladribine, interferon-beta, the excipient(s) of
             the study medications, or to gadolinium- diethylenetriamine penta-acetic acid (DTPA)

          -  Participant has any renal condition that would preclude the administration of
             gadolinium (for example acute or chronic severe renal insufficiency (glomerular
             filtration rate [GFR] less than 30 milliliter per minute per 1.73 square meter
             [mL/min/1.73 m^2])

          -  Participant has a history of chronic or clinically significant hematological
             abnormalities

          -  Participant has a history of active or chronic infectious disease or any disease that
             compromises immune function (for example human immunodeficiency virus positive [HIV+],
             human T-lymphotrophic virus [HTLV-1], Lyme disease, latent tuberculosis infection
             [LTBI] or TB, insulin-dependent diabetes).

          -  Participant has previously been screened in this study (signed an informed consent)
             and then withdrawn

          -  Participant has received any immunomodulatory or immunosuppressive therapy) at any
             time prior to Study Day 1, 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
             (for example natalizumab, alemtuzumab/Campath, anti-cluster of differentiation 4
             [CD4]), intravenous immunoglobulin G (IVIG), cytokines or anti-cytokine therapy

          -  Participant has received experimental MS treatment

          -  Participant has a history of alcohol or drug abuse

          -  Participant has intolerance or any contraindication to both paracetamol
             (acetaminophen) and ibuprofen

          -  Participant has inability to administer subcutaneous injections either by self or by
             caregiver

          -  Participant 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)

          -  Participant has a positive stool hemoccult test at Screening