E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with a first clinical demyelinating event (Clinically Isolated Syndrome (CIS)) at high risk of converting to Multiple Sclerosis (MS) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028245 |
E.1.2 | Term | Multiple sclerosis |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study, which will be determined during the Initial Treatment Period, 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. |
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E.2.2 | Secondary objectives of the trial |
• Evaluate the effect of oral cladribine on the time to conversion to Clinical Definite Multiple Sclerosis (CDMS) according to the Poser criteria, defined by either a second attack or a sustained increase in EDSS score in subjects with a first clinical demyelinating event at high risk of converting to MS • Evaluate the effect of oral cladribine on selected MRI parameters and disease progression in subjects with a first clinical demyelinating event suggestive of MS • Evaluate the safety and tolerability of treatment with oral cladribine in subjects with a first clinical demyelinating event suggestive of MS • Evaluate the impact of CIS and oral cladribine on select patient-reported outcomes domains of the adapted Multiple Sclerosis Quality of Life (MSQOL-54) Scale and Treatment Satisfaction Scale. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 Section 6.2.1 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 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 11. 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. NOTE: Confirmation that the subject is not pregnant must be established by a negative serum human chorionic gonadotropin (hCG) pregnancy test within 28 days of 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.
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E.4 | Principal 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) 23. Have a positive stool heme-occult test at Screening |
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E.5 End points |
E.5.1 | Primary end point(s) |
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). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 130 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |