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    Summary
    EudraCT Number:2008-004954-34
    Sponsor's Protocol Code Number:28981
    National Competent Authority:Slovakia - SIDC (Slovak)
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-09-09
    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 ConcernedSlovakia - SIDC (Slovak)
    A.2EudraCT number2008-004954-34
    A.3Full title of the trial
    Double-blind extension of the study 27025 (REFLEX) to obtain long-term follow-up data in patients with clinically definite MS and patients with a first demyelinating event at high risk of converting to MS, treated with Rebif® New Formulation (REFLEXION)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Long-term Follow-Up of Patients Who Participated in Study 27025 (REFLEX)
    A.3.2Name or abbreviated title of the trial where available
    REFLEXION
    A.4.1Sponsor's protocol code number28981
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00813709
    A.7Trial is part of a Paediatric Investigation Plan No
    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 supportMerck Serono S.A. - Geneva
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck KGaA
    B.5.2Functional name of contact pointCommunication Center Merck KGaA
    B.5.3 Address:
    B.5.3.1Street AddressFrankfurter Strasse 250
    B.5.3.2Town/ cityDarmstadt
    B.5.3.3Post code64293
    B.5.3.4CountryGermany
    B.5.4Telephone number+496151 725200
    B.5.5Fax number+496151 722000
    B.5.6E-mailservice@merck.de
    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.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    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.3.10 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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 Yes
    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 of high risk of converting to Multiple Sclerosis or subjects already converted to Multiple Sclerosis.
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 13.1
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective: to investigate whether RNF treatment initiated after the first clinical event versus delayed treatment results in the prolongation of time to CDMS conversion up to Month 36 since randomisation in study 27025.
    E.2.2Secondary objectives of the trial
    · To investigate whether RNF treatment initiated after the first clinical event versus delayed treatment results in the prolongation of time to CDMS conversion up to Month 60 since randomisation in study 27025.
    · To investigate whether RNF treatment initiated after the first clinical event versus delayed treatment delays disability (including development of secondary progressive MS) and reduces disease activity (including the annual relapse rate) in the long term (up to Month 36 and up to Month 60 since randomisation in study 27025).
    · To assess the long-term safety profile of RNF (up to Month 36 and up to Month 60 since randomisation in study 27025).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    All of the following criteria must be met for inclusion of a subject into the trial:
    · Reach scheduled End of Study in study 27025 (completion of 24 months participation),
    · Medical assessment by the Investigator/treating physician from study 27025 that there is no objection to the subject’s participation in this extension trial considering the medical experience from study 27025. Special attention should be given to laboratory abnormalities and clinically significant liver, renal and bone-marrow dysfunction,
    · If female, subject must:
    · be neither pregnant nor breast-feeding, nor attempting to conceive,
    · 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,
    · Subject is willing to follow study procedures,
    · Subject has given written informed consent.
    E.4Principal exclusion criteria
    Subjects are to be excluded from enrolment into the trial if they fulfill any of the following exclusion criteria:
    · Subject has any disease other than MS that could better explain the subject’s signs and symptoms,
    · Subject has a primary progressive course of MS,
    · Subject has total bilirubin > 2.5 times upper limit of normal at both Month 24 and at the previous visit (i.e. Month 21) (subjects with > 2.5 times upper limit of normal at Month 24 only are eligible for enrollment and should be managed as per label recommendations until normalisation of the value),
    · Subject has total aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase > 2.5 times the upper limit of normal values at both Month 24 and at the previous visit (i.e. Month 21) (subjects with > 2.5 times upper limit of normal at Month 24 only are eligible for enrollment and should be managed as per label recommendations until normalisation of the value),
    · Subject suffers from another current autoimmune disease,
    · Subject suffers from major medical or 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,
    · 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 a history of alcohol or drug abuse,
    · Subject has previously participated in this study,
    · Subject has moderate to severe renal impairment,
    · Subject is pregnant or lactating,
    · Subject has any medical, psychiatric or other conditions that compromise his/her ability to understand the subject information, to give informed consent, to comply with the study protocol, or to complete the study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the time to conversion to CDMS, defined by either a second attack or a sustained increase (≥1.5 points) in the EDSS score (as defined in study 27025), from randomisation in study 27025 up to Month 36.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 36 months.
    E.5.2Secondary end point(s)
    Secondary endpoints up to Month 36 from randomisation in study 27025:
    .Time to confirmed EDSS progression (≥1.0 point, confirmed during a visit performed 6
    months later) from randomisation in study 27025 up to Month 36.
    .MRI endpoints including, but not limited to:
    .Mean number of combined unique active MRI lesions per subject per scan.
    .Mean number of new T2 lesions per subject per scan.
    .Mean number of new T1 lesions per subject per scan.
    .T2 lesion load.
    .T1 lesion load.
    .Mean number of new Gd-enhancing lesions per subject per scan.
    .Brain volume.
    .Other secondary endpoints including:
    .Percentage of subjects with conversion to McDonald MS.
    .Cognition by means of PASAT.
    .Proportion of relapse-free subjects.
    .EDSS changes from baseline over time.
    .Changes from baseline in MSFC (composite score, timed-25-footwalk, 9-hole-pegtest
    and 3’’PASAT) over time.
    Secondary endpoints up to Month 60 from randomisation in study 27025:
    Time to conversion to CDMS from randomisation in study 27025 up to Month 60.
    .Time to confirmed EDSS progression from randomisation in study 27025 up to Month
    60.
    .All other secondary endpoints described above for up to Month 36 (MRI endpoints and
    other).
    Safety endpoints evaluated up to Month 36 and up to Month 60 from randomisation in
    study 27025 include:
    .Incidence, severity and relationship to the trial drug of AEs,
    .SAEs,
    .AEs leading to permanent treatment discontinuation,
    .Clinically significant changes in laboratory tests (according to laboratory reference
    ranges),
    .Use of concomitant medications,
    .Development of BAbs and NAbs to IFN-beta-1a, and
    .Vital signs.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up to 36 months or up to 60 months
    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.8.1.7.1Other trial design description
    Not applicable
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    The control group is the “delayed treatment” group - subjects randomized to placebo in study 27025
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA46
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Austria
    Belgium
    Bulgaria
    Canada
    Croatia
    Czech Republic
    Estonia
    Finland
    France
    Germany
    Greece
    Israel
    Italy
    Latvia
    Lebanon
    Morocco
    Poland
    Portugal
    Romania
    Russian Federation
    Serbia
    Slovakia
    Spain
    Turkey
    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
    The end of trial is defined as the time point for which the last subject has completed his/her final visit evaluation.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 492
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 267
    F.4.2.2In the whole clinical trial 492
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Not defined in the protocol.
    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 Decision2009-03-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-03-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-09-30
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