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    Summary
    EudraCT Number:2013-002318-11
    Sponsor's Protocol Code Number:109MS306
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-03-20
    Trial 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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-002318-11
    A.3Full title of the trial
    Open-Label, Randomized, Multicenter, Multiple-Dose, Active Controlled, Parallel-Group, Efficacy and Safety Study of BG00012 in Children From 10 to Less Than 18 Years of Age With Relapsing-Remitting Multiple Sclerosis
    Studio in aperto, randomizzato, multicentrico, a dosi multiple, con controllo attivo, a gruppi paralleli, sulla sicurezza e l'efficacia di BG00012 nei bambini di età compresa tra 10 e 18 anni affetti da sclerosi multipla recidivante remittente
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study on the safety and effectiveness of BG00012 in children from 10 to less than 18 years old with a type of Multiple Sclerosis that is called "Relapsing-Remitting Multiple Sclerosis".
    Uno studio sulla sicurezza e l'efficacia di BG00012 in bambini di età compresa tra 10 e 18 anni con un tipo di sclerosi multipla che si chiama "sclerosi multipla Recidivante-remittente"
    A.4.1Sponsor's protocol code number109MS306
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/027/2013
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBiogen Idec Research Limited
    B.1.3.4CountryUnited Kingdom
    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 supportBiogen Idec Research Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBiogen Idec Research Limited
    B.5.2Functional name of contact pointClinical Trials - Neurology
    B.5.3 Address:
    B.5.3.1Street AddressInnovation House, 70 Norden Road
    B.5.3.2Town/ cityMaidenhead
    B.5.3.3Post codeSL6 4AY
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailneurologyclinicaltrials@biogenidec.com
    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 No
    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 nameBG00012
    D.3.2Product code BG00012
    D.3.4Pharmaceutical form Gastro-resistant capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDIMETHYL FUMARATE
    D.3.9.1CAS number 624-49-7
    D.3.9.2Current sponsor codeBG00012
    D.3.9.3Other descriptive nameDIMETHYL FUMARATE
    D.3.9.4EV Substance CodeSUB13608MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 AVONEX
    D.2.1.1.2Name of the Marketing Authorisation holderBiogen Idec Ltd
    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 nameAvonex
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular 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 220581-49-7
    D.3.9.3Other descriptive nameINTERFERON BETA-1A
    D.3.9.4EV Substance CodeSUB12440MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number7.5 to 30
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsing-Remitting Multiple Sclerosis
    sclerosi multipla recidivante remittente
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis
    sclerosi multipla
    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 16.1
    E.1.2Level SOC
    E.1.2Classification code 10029205
    E.1.2Term Nervous system disorders
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10063399
    E.1.2Term Relapsing-remitting 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
    The main objectives of the study are as follows:
    • To evaluate the safety, tolerability, and effect on the disease course of BG00012 in pediatric subjects with RRMS, as compared with a disease modifying treatment.
    • To assess PK and PD parameters in a representative subset of pediatric subjects
    • To assess health outcomes and evolution of disability
    valutare la sicurezza, la tollerabilità e l’effetto di BG00012 sul decorso della malattia in soggetti pediatrici con SMRR, rispetto a un trattamento modificante la malattia;
    • valutare i parametri di farmacocinetica (PK) e farmacodinamica (PD) in un sottogruppo rappresentativo di soggetti pediatrici;
    • valutare gli esiti sanitari e l’evoluzione dell’invalidità.
    E.2.2Secondary objectives of the trial
    Not Applicable
    Non applicabile
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible to participate in this study, candidates must meet the following eligibility criteria at the time of randomization (Day 1) or at the timepoint specified in the individual eligibility criterion listed:
    1. Ability of parents or legal guardians to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations. Subjects will provide assent in addition to the parental or guardian consent, as appropriate, as per local regulations.
    2. Males and females aged from 10 to less than 18 years old at the time of informed consent or assent.
    3. Must have a body weight of ≥30 kg.
    4. Must have a diagnosis of RRMS (consensus definition for pediatric RRMS
    [Krupp 2007]).
    5. Must be ambulatory with a baseline EDSS score between 0 and 5.5, inclusive.
    6. Must have experienced at least 1 relapse within the last 12 months prior to Day 1, with a prior brain MRI demonstrating lesions consistent with MS, or show evidence of Gd enhancing lesions of the brain on an MRI performed within the 6 weeks prior to Day 1.
    7. Must be neurologically stable, with no evidence of relapse within 50 days prior to Day 1 and no evidence of corticosteroid treatment within 30 days prior to Day 1.
    8. Subjects of childbearing potential who are sexually active must be willing to practice effective contraception during the study and be willing and able to continue contraception for at least 30 days after their final dose of study treatment.
    1 . Capacità dei genitori o dei tutori legali, di capire lo scopo e i
    rischi dello studio e fornire il consenso informato e l’autorizzazione ad utilizzare le informazioni sanitarie protette ( PHI ) firmati e datati secondo le normative sulla privacy nazionali e locali dei soggetti. I soggetti forniranno un assenso in aggiunta al consenso dei genitori o del tutore , se del caso , come da normative locali.
    2 . Maschi e femmine di età compresa da 10 a meno di 18 anni al momento
    di consenso informato o di assenso .
    3 . Deve avere un peso corporeo ≥ 30 kg .
    4 . Deve avere una diagnosi di SMRR (definizione consenso pediatrico SMRR [ Krupp 2007 ] ) .
    5 . Deve essere ambulatoriale con un punteggio EDSS basale compreso tra 0 e 5.5, inclusiva .
    6 . Aver sperimentato almeno 1 recidiva negli ultimi 12 mesi prima del Day 1 , con una precedente risonanza magnetica cerebrale che dimostri lesioni coerenti con SM , o evidenza di miglioramento delle lesioni Gd del cervello con una Risonanza magnetica effettuata entro le sei settimane precedenti il Giorno 1 .
    7 . Deve essere neurologicamente stabile, senza evidenza di recidiva entro 50
    giorni prima del Day 1 e nessuna evidenza di trattamento con corticosteroidi entro
    30 giorni prima del giorno 1 .
    8 . Soggetti in età fertile che sono sessualmente attivi devono essere
    disposti a praticare una contraccezione efficace durante lo studio ed essere disposti
    e in grado di continuare la contraccezione per almeno 30 giorni dopo la loro ultima
    dose del trattamento in studio.
    E.4Principal exclusion criteria
    Candidates will be excluded from study entry if any of the following exclusion criteria exist at the time of randomization (Day 1) or at the timepoint specified in the individual criterion listed:
    Medical history
    1. Primary progressive, secondary progressive, or progressive relapsing MS (as defined by [Lublin and Reingold 1996]). These conditions require the presence of continuous clinical disease worsening over a period of at least 3 months. Subjects with these conditions may also have superimposed relapses but are distinguished from relapsing remitting subjects by the lack of clinically stable periods or clinical improvement.
    2. Disorders mimicking MS, such as other demyelinating disorders (e.g., acute disseminated encephalomyelitis), systemic autoimmune disorders (e.g., Sjögren disease, lupus erythematosus), metabolic disorders (e.g., dystrophies), and infectious disorders.
    3. History of premalignant or malignant disease. Subjects with basal cell carcinoma that has been completely excised prior to screening will remain eligible.
    4. History of severe allergic or anaphylactic reactions, or known drug hypersensitivity.
    5. History of abnormal laboratory results indicative of any significant endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, renal, and/or any other major disease that would preclude participation in a clinical study.
    6. History of clinically significant cardiovascular, pulmonary, GI, dermatologic, growth, developmental, psychiatric (including depression), neurologic (other than MS), and/or other major disease that would preclude participation in a clinical study.
    7. History of human immunodeficiency virus.
    8. History of drug or alcohol abuse (as defined by the Investigator) within the 2 years prior to Day 1.
    9. An MS relapse that has occurred within 50 days prior to Day 1 AND/OR the subject has not stabilized from a previous relapse prior to Day 1.
    10. History or positive test result at Screening for hepatitis C virus antibody or hepatitis B virus (defined as positive for hepatitis B surface antigen [HBsAg] or hepatitis B core antibody [HBcAb]). Subjects with immunity to hepatitis B from either active vaccination (defined as negative HBsAg, positive hepatitis B surface antibody [HBsAb] and negative HBcAb) or from previous natural infection (defined as negative HBsAg, positive HBsAb IgG, and positive HBcAb) are eligible to participate in the study (definitions are based on the Centers for Disease Control and Prevention [CDC]’s interpretation of the hepatitis B serology panel [CDC 2007]; Appendix 4, Section 25]).
    11. Any of the following abnormal blood test results at Screening:
    - ALT, AST, or gamma glutamyl transferase (GGT) ≥2 × ULN
    - leukocytes <3500/mm3
    - eosinophils >0.7 × 103/μL or >0.7 GI/L
    12. Any of the following abnormal urine tests at Screening confirmed by a second urinalysis approximately 2 weeks later:
    - proteinuria (1+ or greater)
    - hematuria, without known etiology
    - glycosuria, without known etiology
    Note: If a subject has a positive test at Screening and the etiology is known (e.g., due to menses or urinary tract infection in the case of hematuria or due to recent steroid use or elevated serum glucose in the case of glycosuria), a repeat test is not required.
    Treatment history
    13. Any previous treatment with Fumaderm® or BG00012.
    14. Prior treatment with any of the following:
    - total lymphoid irradiation
    - cladribine
    - T-cell or T-cell receptor vaccination
    - any therapeutic monoclonal antibody, with the exception of rituximab (see Exclusion Criterion 15) or natalizumab (see Exclusion Criterion 16)
    15. Prior treatment with any of the following medications within the 12 months prior to Day 1:
    - mitoxantrone
    - cyclophosphamide
    - rituximab
    16. Prior treatment with any of the following medications or procedures within 6 months prior to Day 1:
    - fingolimod
    - teriflunomide
    - natalizumab
    - cyclosporine
    - azathioprine
    - methotrexate
    - mycophenolate mofetil
    - laquinimod
    - IV immunoglobulin
    - plasmapheresis or cytapheresis
    17. Prior treatment with any of the following within 3 months prior to Day 1:
    - glatiramer acetate
    - interferon-alpha
    - interferon β (subjects who are positive for neutralizing antibodies to interferon-β may receive interferon-β treatment up to 2 weeks prior to Day 1)
    18. Treatment with any of the following medications within 30 days prior to Day 1:
    - steroids (IV or oral corticosteroid treatment, including agents that may act through the corticosteroid pathway [e.g., low dose naltrexone])
    - 4-aminopyridine or related products (except subjects on a stable dose of controlled-release fampridine for 3 months)
    19. Current enrollment in any other investigational drug study or participation in any other investigational study within the 6 months prior to Day 1.
    1 . MS progressiva primaria , secondaria o progressiva recidivante
    (come definito da [ Lublino e Reingold 1996 ] ). Queste condizioni richiedono
    la presenza di malattia in continuo peggioramento per un periodo di
    almeno 3 mesi. I soggetti con queste condizioni possono anche avere
    ricadute sovrapposte ma si distinguono dai soggetti con recidivante remittente
    dalla mancanza di periodi clinicamente stabili o miglioramento clinico. 2 . Patologie che mimano la MS , come altri disturbi demielinizzanti (ad esempio,
    encefalomielite acuta disseminata), malattie autoimmuni sistemiche
    (ad esempio, malattia di Sjogren , lupus eritematoso), disturbi metabolici (ad esempio ,
    distrofie), e disturbi infettivi. 3 . Storia di malattia pre-maligna o maligna. I soggetti con carcinoma cellule basali che è stato completamente asportato prima dello screening rimangono elegibili. 4 . Storia di reazioni allergiche o anafilattiche gravi, o ipersensibilità nota al farmaco. 5 . Storia di risultati di laboratorio anomali indicativi di una significativa malattia
    endocrinologica, ematologica, epatica, immunologica, metabolica, urologica,
    renale, e / o qualsiasi altra malattia importante che impediscono la partecipazione
    in uno studio clinico. 6 . Storia di malattia cardiovascolare clinicamente significativo, polmonare, gastrointestinale, dermatologica, crescita, sviluppo, psichiatrica (compresa
    depressione), neurologica (diversa da MS), e / o altra malattia grave
    che potrebbe precludere la partecipazione a uno studio clinico. 7 . Storia del virus dell'immunodeficienza umana. 8 . Storia di droga o alcool (come definito dallo Sperimentatore) entro i 2 anni precedenti il Giorno 1. 9 . Una recidiva di SM che si è verificata entro 50 giorni prima del giorno 1 E / o il soggetto non si è stabilizzato da una precedente recidiva prima del Giorno 1 . 10 . Storia o risultato positivo allo screening per il virus dell'epatite C virus dell'epatite B o anticorpo (definita come positiva per superficie dell'epatite B antigene [ HBsAg ] o anticorpo nucleo dell'epatite B [ HBcAb ]). I soggetti con immunità all’epatite B sia da vaccinazione attiva ( definita come HBsAg negativo, epatite B positivo anticorpi di superficie [ HBsAb ] e HBcAb negativo) o da una infezione precedente (definito come HBsAg negativo, IgG HBsAb positivo, e HBcAb positivo) sono idonei a partecipare allo studio (definizioni si basano sulle Centers for Disease Interpretazione Controllo e Prevenzione [ CDC ] 's della sierologia dell'epatite B pannello [ CDC 2007 ], appendice 4, punto 25 ] ) . 11 . Uno dei seguenti risultati dei test del sangue anomali allo screening : - ALT, AST, o gamma glutamil transferasi ( GGT ) ≥ 2 × ULN - Leucociti < 3500/mm3 - Eosinofili > 0,7 × 103/μL o> 0,7 GI / L 12 . Uno dei seguenti esami delle urine anormali allo screening confermati da
    un secondo esame delle urine circa 2 settimane più tardi : - Proteinuria ( 1+ o superiore) - Ematuria , senza eziologia nota - Glicosuria , senza eziologia nota Nota: se un soggetto ha un test positivo allo screening e l'eziologia è nota (ad esempio, a causa di mestruazioni o infezione del tratto urinario, nel caso di
    ematuria o per recente uso di steroidi o elevata glicemia nel caso di glicosuria), non è richiesto ripetere il test. 13 . Qualsiasi precedente trattamento con Fumaderm ® o BG00012 . 14 . Un precedente trattamento con uno dei seguenti : - Irradiazione linfoide totale - cladribina - Vaccinazione recettore delle cellule T o T - cellule - Qualsiasi anticorpo monoclonale terapeutico , ad eccezione di Rituximab
    ( vedi esclusione Criterio 15) o natalizumab ( vedi esclusione Criterio 16) 15 . Un precedente trattamento con uno qualsiasi dei seguenti farmaci entro le 12
    mesi precedenti il 1 ° giorno : - mitoxantrone - ciclofosfamide - rituximab 16 . Un precedente trattamento con uno qualsiasi dei seguenti farmaci o procedure
    nei 6 mesi precedenti il Giorno 1: - fingolimod - teriflunomide - natalizumab - ciclosporina - azatioprina - methotrexate - Micofenolato - laquinimod - IV immunoglobuline - Plasmaferesi o citaferesi 17 . Un precedente trattamento con una qualsiasi dei seguenti entro 3 mesi prima il
    giorno 1: - Glatiramer acetato - Interferone - alfa - Β interferone (soggetti che sono positivi per anticorpi neutralizzanti interferone - β possono ricevere il trattamento con interferone - β fino a 2 settimane prima del Giorno 1) 18 . Il trattamento con uno qualsiasi dei seguenti farmaci entro 30 giorni prima
    al Giorno 1: - Steroidi (trattamento con corticosteroidi IV o per via orale, compresi gli agenti che possono agire attraverso la via corticosteroide [ad esempio, naltrexone a basso dosaggio ] ) - 4 aminopiridina o prodotti correlati ( ad eccezione di soggetti in dose stabile per 3 mesi di fampridina a rilascio controllato) 19 . L'iscrizione ufficiale in qualsiasi altro studio con farmaco sperimentale o
    partecipazione a qualsiasi altro studio sperimentale nei 6 mesi precedenti
    al giorno 1.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is the proportion of subjects free of new or newly enlarging T2 hyperintense lesions on brain MRI scans at Week 96.
    l’endpoint primario dello studio consiste nella percentuale di soggetti privi di lesioni iperintense in T2 nuove o ingranditesi di recente evidenziate dalle RMI cerebrali alla Settimana 96.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 1 (baseline visit), weeks 24, 48, 72, 96
    Giorno 1 (visita basale), settimane 24, 48, 72, 96
    E.5.2Secondary end point(s)
    The secondary endpoints of this study are as follows:
    • Number of new or newly enlarging T2 hyperintense lesions on brain MRI scans at Weeks 24 and 96
    • Proportion of subjects free of new or newly enlarging T2 hyperintense lesions on brain MRI scans at Weeks 24 and 48
    • Proportion of subjects free of new MRI activity (i.e., free of Gd enhancing and free of new or newly enlarging T2 MRI lesions on brain MRI scans) at Weeks 24, 48, and 96
    • Time to first relapse
    • Proportion of subjects free of relapse up to Week 96
    • Annualized relapse rate at Weeks 48 and 96
    • Incidence of AEs and serious adverse events (SAEs), including prospective follow up of flushing, nausea, abdominal pain, and diarrhea
    • Vital signs, electrocardiograms (ECGs), and changes in clinical laboratory data, including liver function, renal function, hematologic, and coagulation parameters
    • BG00012 PK parameters derived from PK subset data analysis: area under the concentration time curve from time 0 to 10 hours (AUC0 10), maximum observed plasma concentration (Cmax), time to reach maximum observed plasma concentration (Tmax), lag time, elimination half-life (t½), apparent clearance (Cl/F), and apparent volume of distribution (V/F)
    • PD parameters, derived from PD subset data analysis: changes in the nuclear factor (erythroid derived 2) like 2 activation pathway markers nicotinamide adenine dinucleotide phosphate [NAD(P)H] dehydrogenase, quinone 1 (NQO 1) and heme oxygenase 1 (HO 1)
    • Fatigue as measured by the PedsQL Multidimensional Fatigue Scale scores
    • Quality of Life as measured by the PedsQL
    • Change from baseline to Week 96 in the EDSS score
    • numero di lesioni iperintense in T2 nuove o ingranditesi di recente evidenziate dalle RMI cerebrali alle Settimane 24 e 96;
    • percentuale di soggetti privi di lesioni iperintense in T2 nuove o ingranditesi di recente evidenziate dalle RMI cerebrali alle Settimane 24 e 48;
    • percentuale di soggetti privi di nuova attività evidenziata dalla RMI (ovvero, privi di lesioni captanti il Gd e privi di lesioni in T2 nuove o ingranditesi di recente evidenziate dalle RMI cerebrali) alle Settimane 24, 48 e 96;
    • tempo alla prima recidiva;
    • percentuale di soggetti privi di recidiva fino alla Settimana 96;
    • tasso di recidive su base annua alle Settimane 48 e 96;
    • incidenza di eventi avversi (AE) ed eventi avversi gravi (SAE), incluso follow-up prospettico di vampate di calore, nausea, dolore addominale e diarrea;
    • segni vitali, elettrocardiogrammi (ECG) e variazioni nei dati clinici di laboratorio, inclusi il monitoraggio di funzionalità epatica, funzionalità renale, parametri ematologici e della coagulazione;
    • parametri PK di BG00012 derivati dall’analisi dei dati del sottoinsieme PK: area sottesa alla curva della concentrazione/tempo da 0 a 10 ore (AUC0-10), concentrazione plasmatica massima osservata (Cmax), tempo al raggiungimento della concentrazione plasmatica massima osservata (Tmax), ritardo temporale, emivita di eliminazione (t½), clearance apparente (Cl/F) e volume di distribuzione apparente (V/F);
    • parametri PD, derivati dall’analisi dei dati del sottoinsieme PD: variazioni nel fattore nucleare (eritroide-derivato 2) come 2 marcatori della via di attivazione (Nrf2), nicotinammide adenina dinucleotide fosfato ridotto [NAD(P)H] deidrogenasi, chinone ossidoreduttasi 1 (NQO-1) ed eme ossigenasi 1 (HO-1);
    • affaticamento misurato mediante i punteggi della Scala multidimensionale per la valutazione della fatica PedsQL™ (Pediatric Quality of Life Inventory, [Inventario della qualità della vita in età pediatrica]);
    • qualità della vita misurata mediante la scala PedsQL;
    • variazione dal basale alla Settimana 96 nel punteggio della Scala di invalidità espansa (EDSS, Expanded Disability Status Scale);
    E.5.2.1Timepoint(s) of evaluation of this end point
    The various secondary endpoints will be measured throughout the study as defined by the Schedule of Events. Specifically there are visits at Day 1 (baseline) weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 and a safety follow-up visit at week 100. There is also a safety telephone call at week2.
    I vari end point secondari saranno misurati nel corso dello studio come definito nella schedule of eventsi. In particolare ci sono visite al Day 1 (basale) settimane 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 e una visita di follow-up di sicurezza alla settimana 100. C'è anche una telefonata di sicurezza alla week2.
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    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
    Belgium
    Czech Republic
    Denmark
    France
    Hungary
    Italy
    Poland
    Serbia
    Sweden
    Ukraine
    United Kingdom
    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
    LVLS: The end of study is last subject, last visit for final collection of data for the primary outcome
    LVLS
    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 months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    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 Yes
    F.1.1Number of subjects for this age range: 142
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 20
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 122
    F.1.2Adults (18-64 years) No
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 127
    F.4.2.2In the whole clinical trial 142
    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)
    Subjects who choose not to enroll in the extension study will have a Safety Follow-Up Visit 4 weeks after taking the final dose. Subjects who withdraw prematurely will complete the Early Withdrawal Visit and the Safety Follow-Up Visit 4 weeks after taking their final dose.
    I soggetti che scelgono di non essere arruolati nello studio di estensione faranno una visita di Follow-Up Visita di sicurezza quattro settimane dopo l'assunzione della dose finale. I soggetti che si ritirano prematuramente completeranno la visita di ritiro anticipato e la visita di follow-up di sicurezza quattro settimane dopo aver assunto la loro dose finale
    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 Decision2014-04-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-05-13
    P. End of Trial
    P.End of Trial StatusOngoing
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