The goal of this study is to evaluate the safety, tolerability and effectiveness of oral
cladribine when taken in combination with Interferon-beta therapy for the treatment of MS.
This study will randomize 200 subjects from approximately 50 sites located world-wide, who
have experienced at least one relapse while taking Interferon-beta therapy within 48 weeks
prior to Screening, irrespective of disability progression. Secondary progressive multiple
sclerosis (SPMS) patients, who are still experiencing relapses, and patients who have
received disease modifying drugs (DMDs), other than Interferon-beta therapy, during their MS
treatment history, but are currently on Interferon-beta therapy and have experienced active
MS symptoms (at least 1 relapse) during the 48 weeks prior to Screening, may also be
enrolled.
Subjects will be randomised in a 2: 1 fashion to receive up to 4 cycles of oral cladribine or
matching placebo in combination with Interferon-beta therapy. Total subject participation is
104 weeks.
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 (see Exclusion Criteria);
- If female, must either:
- 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 than 1% 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.
- If male, he 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 in this protocol; and
- Voluntarily provide written informed consent, including, for USA, subject
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 subject may withdraw consent at any time without prejudice to
their future medical care.
Confirmation that the subject is not pregnant must be established by a negative serum human
chorionic gonadotropin (hCG) pregnancy test within 28 days prior to Study Day 1 and a
negative urine pregnancy test on Study Day 1. A pregnancy test is not required if the
subject is post-menopausal or surgically sterilized.
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.
