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    Summary
    EudraCT Number:2006-002982-38
    Sponsor's Protocol Code Number:27025
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2006-09-14
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2006-002982-38
    A.3Full title of the trial
    A phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial of Rebif New Formulation (44 mcg tiw and 44 mcg ow) in subjects at high risk of converting to Multiple Sclerosis
    A.3.2Name or abbreviated title of the trial where available
    Rebif FLEXible dosing in early Multiple Sclerosis (REFLEX)
    A.4.1Sponsor's protocol code number27025
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMerck Serono S.A.-Geneva, an affiliate of Merck KGaA Darmstadt, Germany
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Rebif
    D.2.1.1.2Name of the Marketing Authorisation holderSerono Europe Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameInterferon-beta 1a FBS-free/HSA free, RNF
    D.3.2Product code Not Applicable
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNInterferon-beta 1a
    D.3.9.1CAS number NA
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number44
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Subjects at high risk of converting to Multiple Sclerosis
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.0
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to evaluate the effect of Rebif New Formulation 44 mcg (tiw and ow) versus placebo on the time to conversion to McDonald MS in patients with a first clinical demyelinating event at high risk of converting to MS.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study include the assessment of secondary efficacy endpoints and safety:

    The main secondary objectives is to assess:
    · The time to conversion to CDMS

    Other secondary objectives are:
    · Number of combined unique active MRI lesions
    · Number of new T2 lesions
    · Number of new T1 lesions
    · Number of new Gd-enhancing lesions
    . T2 lesion volume
    . T1 hypointensive lesion volume
    . T1 Gd-enhancing lesion volume
    · Cognition by means of PASAT
    · Relapse rate
    · EDSS
    · MSFC
    · Development of BAbs and NAbs
    · Safety, including AEs, SAEs and laboratory parameters
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Optical Coherence Tomography (OCT) sub-study as per appendix L in the protocol dated 11 April 2007.
    The goal of this exploratory sub-study is to investigate the axonal degeneration in patients enrolled into the REFLEX study, who are initially diagnosed with CIS, by measuring the RNFL thickness with OCT.
    The three objectives of this exploratory sub-study are:
    1. To describe the axonal degeneration at baseline, after a first event suggestive of MS
    2. To describe the correlation of axonal degeneration with ‘traditional’ MS related
    assessments (e.g. MRI, EDSS…)
    3. To describe changes in RNFL thinning over time
    E.3Principal inclusion criteria
    · Subject with a single, first clinical event suggestive of MS within 60 days prior to SD1, which is the day of randomisation (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;
    · Subject has at least two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 mm, at least one of which is ovoid or periventricular or infratentorial;
    · EDSS 0 - 5.0 at at least one time point during the screening period before start of treatment;
    · Subject is between 18 and 50 years old, inclusive;
    · Subject is willing to follow study procedures;
    · Subject has given written informed consent;
    · If female, subject must:
    a) be neither pregnant nor breast-feeding nor attempting to conceive
    b) use a highly effective method of contraception. 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 vasectomised partner.*

    *Note for subjects using a hormonal contraceptive method: No formal drug interaction studies have been carried out with IFN-beta-1a or HSA free IFN beta 1a. As interferons have been reported to exert an inhibitory activity on hepatic microsomal enzymes, it is unlikely that the clearance of oral contraceptives would be increased and result in decreased efficacy. In over 10,000 patient-years of clinical trial experience with Rebif®, there has never been any indication of an interaction with oral contraceptives.
    E.4Principal exclusion criteria
    · Subject has a diagnosis of Multiple Sclerosis (per McDonald criteria 2005);
    · Subject has any other disease that could better explain the patient’s signs and symptoms;
    · Subject has complete transverse myelitis or bilateral optic neuritis;
    · Subject uses or has used any other approved MS DMD;
    · Subject has used any investigational drug or undergone an experimental procedure within 12 weeks prior to SD1;
    · Subject received oral or systemic corticosteroids or ACTH within 30 days prior to SD1;
    · Subject has total bilirubin > 2.5x upper limit of normal,
    · Subject has total aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase > 2.5 times the upper limit of normal values;
    · Subject has inadequate bone marrow reserve, defined as a total white blood cell count < 3.0 x 109/L, platelet count < 75 x 109/L, haemoglobin < 100 g/L.
    · Subject suffers from current autoimmune disease;
    · Subject suffers from major medical or psychiatric illness (including history of 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;
    · Subject has a history of seizures not adequately controlled by treatment;
    · Subject has cardiac disease, such as angina, congestive heart failure or arrhythmia;
    · Subject has a known allergy to IFN-beta or the excipient(s) of the study medication;
    · Subject has any condition that could interfere with the MRI evaluation;
    · Subject has a known allergy to gadolinium-DTPA;
    · Subject has previously participated in this study;
    · Subject has participated in any clinical trial within the past 6 months prior to SD1;
    · Subject has received any immunomodulatory or immunosuppressive therapy at any time prior to SD1, 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), IvIg, cytokines or anti-cytokine therapy;
    · Subject has received any experimental MS treatment prior to SD1, including, but not limited to, any statins (if given to prevent MS) and pentoxyfilline;
    · Subject has a history of alcohol or drug abuse;
    · Subject has intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen;
    · Inability to administer subcutanteous injections either by self or by caregiver;
    · Subject has moderate to severe renal impairment.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the time to conversion to MS (from randomization), according to the revised McDonald criteria (2005). Patients who do not convert are considered as censored for analysis.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other 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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA71
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial 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
    Database lock, as this provides for a single and conservative definition across all study sites
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 203
    F.4.2.2In the whole clinical trial 480
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2006-10-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-11-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-09-16
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