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A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center Clinical Trial of Oral Cladribine in Subjects With a First Clinical Event at High Risk of Converting to MS

Phase 3
18 Years
55 Years
Not Enrolling
Multiple Sclerosis

Thank you

Trial Information

A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center Clinical Trial of Oral Cladribine in Subjects With a First Clinical 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

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 Poser criteria.

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.

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. Hematological parameters must be normal (as defined by the central lab)

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 intrauterine 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

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 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

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 immunoglobulin 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Time to conversion to clinically definite MS (from randomization), according to the Poser Criteria, defined by either a 2nd attack or a sustained increase (³1.5 points) in the EDSS score which will be determined during the initial treatment period.

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Bettina Stubinski, MD

Investigator Role:

Study Director

Investigator Affiliation:

Merck Serono S.A., Geneva


United States: Food and Drug Administration

Study ID:




Start Date:

October 2008

Completion Date:

June 2012

Related Keywords:

  • Multiple Sclerosis
  • Clinically Isolated Syndrome (CIS)
  • Early MS
  • Multiple Sclerosis
  • Multiple Sclerosis
  • Sclerosis



Research SiteBeverly, Massachusetts