A Phase 2 Study of Cladribine Add-on to Interferon-beta (IFN-beta) Therapy in Multiple Sclerosis (MS) Subjects With Active Disease (ONWARD)
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Intervention: Cladribine; Placebo; Interferon-beta (IFN-beta)
Intervention description: Participants were administered with cladribine tablets orally as cumulative dose.; Participants were administered with placebo orally.; Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.
Intervention MeSH terms: Interferons; Interferon-beta; Cladribine; Interferon beta-1b
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 172.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Multiple Sclerosis; Relapsing forms; Interferon-beta therapy

Summary:

      The goal of this study was to evaluate the safety, tolerability and effectiveness of oral
      cladribine when taken in combination with Interferon-beta (IFN-beta) therapy for the
      treatment of multiple sclerosis (MS).

      This study randomized around 200 participants from approximately 50 sites located world-wide,
      who have experienced at least one relapse while taking IFN-beta therapy within 48 weeks prior
      to Screening, irrespective of disability progression. Secondary progressive multiple
      sclerosis (SPMS) participants, who were still experiencing relapses, and participants who
      have received disease modifying drugs (DMDs), other than IFN-beta therapy, during their MS
      treatment history, but were currently on IFN-beta therapy and have experienced active MS
      symptoms (at least 1 relapse) during the 48 weeks prior to Screening, were enrolled.

      Participants were randomized in a 2:1 fashion to receive up to 4 cycles of oral cladribine or
      matching placebo in combination with IFN-beta therapy. Participants who completed the
      double-blind portion of the study were invited to participate in an open-label extension
      phase of matching study design.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Be male or female, 18 to 65 years of age (inclusive)

          -  Weigh between 40 to 120 kilogram (kg), (inclusive)

          -  Have definite MS, as confirmed by the revised McDonald criteria 2005, and have
             relapsing forms of MS, such as relapsing-remitting multiple sclerosis (RRMS) or SPMS
             with superimposed relapses

          -  Have experienced at least one relapse within 48 weeks prior to Screening, while
             receiving IFN-beta treatments (Rebif® 44mcg three times a week, subcutaneously;
             Avonex®30 mcg every week, intramuscular; or Betaseron® 250 mcg every other day,
             subcutaneously)

          -  Have a minimum time on IFN-beta therapy of 48-consecutive weeks prior to Screening.
             Participants who switched from one IFN-beta 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-beta 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 study day 1 (SD 1)

               -  Hemoglobin=11.6 to 16.2 gram per deciliter (g/dL)

               -  Leukocytes (total white blood cells [WBC])=4.1 to 12.3*10^3 per microliter (/UL)

               -  Absolute lymphocytes count (ALC)= 1.02 to 3.36*10^3/UL

               -  Absolute neutrophil count (ANC)=2.03 to 8.36*10^3/UL

               -  Platelet count=140 to 450*10^3/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

          -  Have an expanded disability status scale (EDSS) from 1.0-5.5, inclusive

          -  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

          -  If female, 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 6 months (6 menstrual cycles) following completion of the last
                  dose of study medication. A highly effective method of contraception is defined
                  as one 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 (IUDs), sexual abstinence or a
                  vasectomized partner. For the purpose of this trial, women of childbearing
                  potential are defined as: All female participants after puberty unless they are
                  post-menopausal for at least 2 years, or are surgically sterile

          -  If male, must be willing to use contraception to avoid pregnancies throughout the
             entire duration of 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

          -  Have not met any of the exclusion criteria outlined below; and

          -  Have voluntarily provided written informed consent, 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, and with the understanding that the participant may withdraw
             consent at any time without prejudice to future medical care

          -  Other protocol defined inclusion criteria may apply

        Exclusion Criteria:

          -  Has primary progressive multiple sclerosis (PPMS) or SPMS without relapses forms

          -  Has prior or current malignancy other than medically documented complete excision of
             basal cell skin cancer no less than 5 years prior to Screening

          -  Has a history of chronic or clinically significant hematological abnormalities

          -  Prior use of cladribine, fingolimod, teriflunimide, laquinimod, 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 SD
             1

          -  Treatment with IVIG within 30 days of Screening

          -  Treatment with oral or parenteral corticosteroids 30 days of Screening

          -  Treatment with adrenocorticotropic hormone within 28 days prior to SD 1

          -  Use of any investigational drug (other than Rebif® New Formulation [RNF], Avonex® or
             Betaferon®) or experimental procedure within 6 months prior to SD 1

          -  Has inadequate liver function, defined by a total bilirubin, aspartate
             aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase greater
             than 2.5 times the upper limit of the normal values

          -  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

          -  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 participant or could affect compliance with the study
             protocol

          -  Has history of active or chronic infectious disease or any disease which compromises
             immune function (for example, human immunodeficiency virus [HIV]+, human
             T-lymphotropic virus [HTLV-1], Lyme disease, LTBI or TB)

          -  Has an allergy or hypersensitivity to gadolinium, to cladribine or any of its
             excipients, or IFN-beta or any of its excipient(s)

          -  Has any renal condition that would preclude the administration of gadolinium (for
             example, acute or chronic severe renal insufficiency [glomerular filtration rate less
             than 30 milliliter per minute {mL/min} per 1.73 square meter {m^2}])

          -  Has a positive stool hemoccult test at Screening

          -  Has a history of seizures not adequately controlled by treatment