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    Summary
    EudraCT Number:2011-006262-40
    Sponsor's Protocol Code Number:215MS201
    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:2013-04-08
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2011-006262-40
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Ranging Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Subjects with Relapsing Forms of Multiple Sclerosis When Used Concurrently with Avonex®
    Studio randomizzato, in doppio cieco, controllato con placebo, a gruppi paralleli, di dose-ranging per verificare l'efficacia, la sicurezza, la tollerabilità e la farmacocinetica di BIIB033 in soggetti con forme recidivanti di sclerosi multipla quando usato in combinazione con Avonex®
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the safety and efficacy of BIIB033 in patients with relapsing forms of multiple sclerosis when used concurrently with Avonex®
    Studio per valutare la sicurezza e l’efficacia di BIIB033 in pazienti con forme recidivanti di sclerosi multipla quando usato insieme a Avonex.
    A.4.1Sponsor's protocol code number215MS201
    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 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 point215MS201 Clinical Trial Team
    B.5.3 Address:
    B.5.3.1Street AddressInnovation House, 70 Norden Road
    B.5.3.2Town/ cityMaidenhead, Berkshire
    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 nameBIIB033
    D.3.2Product code BIIB033
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeBIIB033
    D.3.9.3Other descriptive nameHuman anti-LINGO-1 monoclonal antibody
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.IMP: 2
    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 Avonex
    D.2.1.1.2Name of the Marketing Authorisation holderBiogen Idec 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 nameAVONEX
    D.3.4Pharmaceutical form Solution for 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.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsing forms of multiple sclerosis
    Forme di sclerosi multipla recidivante
    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 14.1
    E.1.2Level PT
    E.1.2Classification code 10063400
    E.1.2Term Secondary progressive multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    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 primary objective of the study is to evaluate the efficacy of BIIB033
    in subjects with active relapsing MS when used concurrently with
    Avonex.
    E.2.1 Obiettivo principale:
    L'obiettivo primario dello studio è valutare l'efficacia di BIIB033 in soggetti con sclerosi multipla recidivante attiva, se usato in concomitanza con Avonex.

    Gli obiettivi secondari di questo studio, per la popolazione specifica in studio, consistono nel valutare la sicurezza, tollerabilità e la farmacocinetica di popolazione di BIIB033 usato in concomitanza con Avonex.

    E.2.2Secondary objectives of the trial
    Secondary objectives of this study in this study population are to assess
    the safety, tolerability, and population PK of BIIB033 when used
    concurrently with Avonex.
    Gli obiettivi secondari di questo studio, per la popolazione specifica in studio, consistono nel valutare la sicurezza, tollerabilità e la farmacocinetica di popolazione di BIIB033 usato in concomitanza con Avonex.

    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Optional lumbar puncture substudy: CSF will be collected to assess the
    modulation of potential PD/other biomarker that may be related to
    BIIB033 activity or MS disease activity.
    Sottostudio opzionale relativo alla puntura lombare contenuto nel protocollo principale dal titolo:
    Studio randomizzato, in doppio cieco, controllato con placebo, a gruppi paralleli, di dose-ranging per verificare l'efficacia, la sicurezza, la tollerabilità e la farmacocinetica di BIIB033 in soggetti con forme recidivanti di sclerosi multipla quando usato in combinazione con Avonex®. Versione 2, 19 Dicebre 2012.
    Obiettivi:
    Il liquido cerebrospinale sarà raccolto per valutare la modulazione della farmacodinamica/di un altro biomarcatore potenzialmente correlati all'attività di BIIB033 o all'attività della malattia SM.
    E.3Principal inclusion criteria
    1. Ability to understand the purpose and risks of the study and provide
    signed and dated Informed Consent Form (ICF) and authorization to use
    protected health information (PHI) in accordance with national and local
    subject privacy regulations.
    2. Aged 18 to 58 years old, inclusive, at the time of informed consent.
    3. Diagnosis of RRMS per the 2005 McDonald's criteria or onset of SPMS
    per the Lublin and Reingold criteria.
    4. For RRMS, subjects must have disease activity as defined by 2 or more
    distinct occurrences of any of the following 3 events within 12 months of
    enrollment: Clinical relapse Gd+ lesion on MRI (brain or spinal cord MRI)
    New T2 lesion on MRI (brain or spinal cord MRI)
    5. For SPMS, subjects must have disease activity as defined by 1 or more
    distinct occurrences of any of the following 2 events within 12 months of
    enrollment: Clinical relapse Gd+ lesion on MRI (brain or spinal cord MRI)
    6. Baseline EDSS score of 2 to 6.
    7. All male and female subjects of childbearing potential must practice
    effective contraception during the study and be willing and able to
    continue contraception for at least 6 months after their last dose of
    study treatment (BIIB033 plus Avonex or placebo plus Avonex).
    1. Capacità di comprendere lo scopo e i rischi dello studio e di fornire il Modulo di consenso informato (ICF) firmato e datato, nonché l'autorizzazione a usare informazioni sensibili sulla propria salute in base alle regolamentazioni nazionali e locali sulla privacy dei soggetti.
    2. Età compresa fra 18 e 58 anni (inclusi) al momento del consenso informato.
    3. Diagnosi di RRMS in base ai criteri McDonald [Polman et al, 2005] o manifestazione di SPMS in base ai criteri Lublin and Reingold [Lublin and Reingold 1996].
    4. Per RRMS i soggetti devono presentare attività della malattia definita come 2 o più occorrenze distinte di uno qualsiasi dei 3 eventi seguenti entro 12 mesi dall'arruolamento:
    • Recidiva clinica
    • Lesione Gadolinio-positivanella RM (RM dell'encefalo o del midollo spinale)
    • Una nuova lesione T2 nella RM (RM dell'encefalo o del midollo spinale)
    5. Per SPMS i soggetti devono presentare attività della malattia definita come 1 o più occorrenze distinte di uno qualsiasi dei 2 eventi seguenti entro 12 mesi dall'arruolamento:
    • Recidiva clinica
    • Lesione Gd+ nella RM (RM dell'encefalo o del midollo spinale)
    6. Punteggio EDSS al baseline da 2 a 6.
    Tutti i soggetti di sesso maschile e femminile potenzialmente fertili devono utilizzare metodi contraccettivi efficaci durante lo studio e accettare di continuare a ricorrere alla contraccezione per almeno 6 mesi dopo l'ultima dose di trattamento sperimentale (BIIB033 più Avonex o placebo più Avonex).
    E.4Principal exclusion criteria
    1. History of abnormal laboratory results that in the opinion of the
    Investigator, are indicative of an significant cardiac, endocrine,
    hematologic, immunologic, metabolic, urologic, pulmonary,
    gastrointestinal, dermatologic, psychiatric, renal, neurologic (other than
    MS) and/or other major disease that would preclude administration of
    BIIB033 and/or Avonex.
    2. Any of the following abnormal blood tests at screening: hemoglobin ≤
    9.0 g/dL platelets ≤100 X 109/L lymphocytes ≤1.0 X 109/L neutrophils
    ≤1.5 X 109/L alanine aminotransferase/serum glutamate pyruvate
    transaminase (ALT/SGPT), aspartate aminotransferase/serum glutamic
    oxaloacetic transaminase (AST/SGOT), or gamma-glutamyl-transferase
    ≥ 2 times the upper limit of normal (ULN) serum creatinine ≥ULN
    3. Treatment with Botox for limb spasticity within 6 months before Day
    1/Baseline.
    4. Plans to undergo elective major procedures/surgeries at any time
    during the study.
    5. Simultaneous participation in another study protocol.
    6. Treatment with any investigational MS drugs within 3 weeks or 5 t1/2
    (whichever is longer) prior to Day 1/Baseline.
    7. Treatment with high dose oral or IV steroids ≤30 days before Day
    1/Baseline.
    8. History of suicidal ideation or an episode of clinically severe
    depression (as determined by the Investigator) within 3 months of
    enrollment. Note: subjects receiving ongoing antidepressant therapy will
    not be excluded from the study unless the medication has been
    increased within the 6 months prior to enrollment.
    9. RRMS subjects with any history of inadequate response to any
    approved (in country of residence) interferon β preparation (e.g.,
    Avonex, Rebif, interferon β-1b, or any generic interferon β). (Inadequate
    response definition: 2 or more distinct occurrences of clinical relapse
    and/or Gd+ lesion on MRI and/or new or non-enhancing lesion on MRI
    within any 12-month period while compliant with interferon β.)
    10. History of human immunodeficiency virus or other immunodeficient
    conditions.
    11. History of positive test result for hepatitis C virus Ab or Hepatitis B
    virus (defined as positive for hepatitis B surface antigen or hepatitis B
    core Ab).
    12. History of drug or alcohol abuse (as defined by the Investigator)
    within 2 years prior to randomization.
    13. History of seizure disorder or unexplained blackouts OR history of a
    seizure within 6 months prior to Baseline.
    14. Female subjects who have a positive pregnancy test, are pregnant,
    or currently breast feeding.
    15. T25FW >30 seconds (any of the 2 tests at Screening).
    16. History of malignancy; however subjects with a history or excised or
    treated basal cell carcinoma or fewer than 3 squamous cell carcinomas
    are eligible to participate in this study.
    17. Renal impairment with a creatinine clearance <80 mL/minute at
    Screening (creatinine clearance estimated by Cockcroft-Gault equation).
    18. In the opinion of the Investigator, a history of clinically significant
    persistent neutralizing Ab against interferon β.
    19. Known intolerance, contraindication to, or history of noncompliance
    with Avonex.
    20. Treatment with fingolimod or investigational sphingosine 1-
    phosphate receptor 1 (S1P1) agonists within 3 months prior to Day
    1/Baseline.
    21. Treatment with natalizumab within 3 months prior to Day
    1/Baseline.
    22. Initiation of treatment or dose adjustment of commercially available
    4-aminopyridine (4-AP) or related products within the last 28 days.
    Note: subjects who have been on a stable dose of commercially available
    4-AP for longer than 28 days are not excluded.
    23. Treatment with any chemotherapeutic agents (e.g., mitoxantrone,
    cyclophosphamide, cladribine) or cell depleting mAbs (e.g., rituximab,
    ocrelizumab, alemtuzumab) within 6 months prior to Day 1/Baseline,
    unless treatment with the chemotherapeutic agent/cell depleting mAbs
    occurs no earlier than 3 months of Day 1/Baseline (i.e., between 3 and 6
    months of Day 1/Baseline) and the subject's white blood cell (WBC)
    count is determined to be within normal range at Screening.
    24. An MS relapse that has occurred within the 90 days prior to Day
    1/Baseline and/or the subject has not stabilized from a previous relapse
    prior to Screening.
    25. Inability to comply with study requirements.
    26. Other unspecified reasons that, in the opinion of the Investigator or
    Biogen Idec, make the subject unsuitable for enrollment.
    • Storia di risultati di laboratorio anomali che secondo lo Sperimentatore sono indicativi di una significativa patologia di natura cardiaca, endocrina, ematologica, immunologica, metabolica, urologica, polmonare, gastrointestinale, dermatologica, psichiatrica, renale, neurologica (diversa dalla Sclerosi Multipla) e/o di altro tipo che potrebbe precludere la somministrazione di BIIB033 e/o Avonex.
    • Una delle seguenti anomalie nelle analisi del sangue allo Screening:
    • emoglobina ≤9,0 g/dl
    • piastrine ≤100 X 109/l
    • linfociti ≤1,0 X 109/l
    • neutrofili ≤1,5 X 109/l
    • alanina aminotransferasi/transaminasi glutammico-piruvica nel siero (ALT/SGPT), aspartato aminotransferasi/transaminasi glutammico-ossalacetica nel siero (AST/SGOT) o gamma glutamil-transferasi ≥ 2 volte il limite superiore alla norma (upper limit of normal=ULN)
    • creatinina nel siero ≥ ULN
    • Trattamento con Botox per la spasticità degli arti nei 6 mesi precedenti il Giorno 1/ Baseline.
    • Previsione di sottoporsi a procedure/operazioni chirurgiche elettive di notevole entità in qualsiasi momento durante lo studio.
    • Partecipazione simultanea a un altro protocollo di studio.
    • Trattamento con un qualsiasi farmaco sperimentale per la Sclerosi Multipla nelle 3 settimane o 5 t1/2 (a seconda della condizione che si protrae più a lungo) prima del Giorno 1/Baseline.
    • Trattamento con steroidi per via endovenosa o orale a dosaggio elevato ≤30 giorni prima del Giorno 1/Baseline.
    • Storia di intenzione suicida o episodio di depressione clinica grave (secondo il giudizio dello Sperimentatore) entro 3 mesi dall'arruolamento. Nota: i soggetti con terapia antidepressiva in corso non saranno esclusi dallo studio a meno che la dose del farmaco non sia stata aumentata nei 6 mesi precedenti l'arruolamento.
    • Soggetti RRMS con una storia di risposta inadeguata a una qualsiasi preparazione approvata (nel Paese di residenza) di interferone β (cioè Avonex, Rebif, interferone β-1b o qualsiasi altro interferone β generico). (Definizione di risposta inadeguata: 2 o più occorrenze distinte di recidiva clinica e/o lesione Gd+ nella RM e/o lesione nuova o non in miglioramento nella RM nell'arco di un periodo di 12 mesi in condizione di trattamento regolare con interferone β).
    • Storia di virus dell'immunodeficienza umana o di altre condizioni di immunodeficienza.
    • Storia di risultato positivo del test per anticorpi (Ab) per il virus dell’epatite C o dell’epatite B (definito come positivo per l’antigene di superficie dell’epatite B o per il core per l’epatite B)
    • Storia di abuso di droga o alcol (in base alla definizione dello Sperimentatore) nei due anni precedenti la randomizzazione.
    • Storia di disturbi epilettici o amnesie inspiegabili OPPURE storia di crisi epilettica nei 6 mesi precedenti il Baseline.
    • Soggetti di sesso femminile con test di gravidanza positivo, in stato di gravidanza o che allattamento al seno.
    • T25FW >30 secondi (uno dei 2 test allo Screening).
    • Storia di neoplasia maligna; tuttavia i soggetti con una storia di carcinoma a cellule basali asportato chirurgicamente o trattato o di meno di 3 carcinomi a cellule squamose sono idonei alla partecipazione a questo studio.
    • Insufficienza renale con clearance della creatinina <80 ml/minuto allo Screening (clearance della creatinina stimata tramite equazione Cockcroft-Gault).
    • A giudizio dello Sperimentatore, una storia di Ab neutralizzanti diretti contro l'interferone β persistente e clinicamente significativa.
    • Intolleranza nota, controindicazione o storia di mancata aderenza al trattamento con Avonex.
    • Trattamento con fingolimod o antagonisti sperimentali del recettore 1 della sfingosina-1-fosfato (S1P1) nei 3 mesi precedenti il Giorno 1/Baseline.
    • Trattamento con natalizumab nei 3 mesi precedenti il Giorno 1/Baseline.
    • Inizio del trattamento o variazione/adeguamento della dose di 4-aminopiridina disponibile in commercio (4-AP) o di prodotti correlati negli ultimi 28 giorni. NOTA: i soggetti che ricevono una dose stabile di 4-AP disponibile in commercio da più di 28 giorni non sono esclusi.
    •Trattamento con agenti chemioterapici (ad es. mitoxantrone, ciclofosfamide, cladribina) o con Anticorpi monoclonali (mAB) (cioè rituximab, ocrelizumab, alemtuzumab) nei 6 mesi precedenti il Giorno 1/Baseline, a meno che il trattamento con l'agente chemioterapico/mAb per l'eliminazione di cellule sia avvenuto non meno di 3 mesi prima del Giorno 1/Baseline (cioè fra 3 e 6 mesi dal Giorno 1/Baseline) e il conteggio dei globuli bianchi del soggetto (WBC) risulti nella norma allo Screening.
    •Una recidiva di Sclerosi Multipla verificatasi nei 90 giorni precedenti il Giorno 1/Baseline e/o la mancata stabilizzazione del soggetto da una precedente recidiva manifestatasi prima dello Screening.
    •Incapacità di aderire/conformarsi ai requisiti dello studio.
    •Altri motivi non specificati che, secondo lo Sperimentatore o Biogen Idec, rendono il soggetto non idoneo all'arruolamento
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoint:
    Percentage of subjects experiencing confirmed improvement of
    neurophysical
    and/or cognitive function over 72 weeks (approximately 18
    months) of treatment as measured by a composite endpoint comprising
    the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk
    (T25FW), 9-Hole Peg Test (9HPT), and (3-Second) Paced Auditory Serial
    Addition Test (PASAT).
    Improvement on neuro-physical and/or cognitive function is defined as
    at least 1 of the following: A ≥1.0 point decrease in EDSS from a baseline
    score of ≤6.0 (decrease sustained for 3 months or greater). A ≥15%
    improvement from baseline in T25FW (improvement sustained for 3
    months or greater). A ≥15% improvement from baseline in 9HPT
    (improvement sustained for 3 months or greater). A ≥15% improvement
    from baseline in PASAT (improvement sustained for 3 months or
    greater).
    I seguenti endpoint di efficacia saranno impiegati per definire l'obiettivo primario:
    Endpoint di efficacia primari:
    Percentuale di soggetti con miglioramento confermato della funzionalità neuro-fisica e/o cognitiva nell'arco di 72 settimane (circa 18 mesi) di trattamento, misurato tramite un endpoint composito comprendente la scala di invalidità espansa (Expanded Disability Status Scale, EDSS), il temponecessario a percorrere 25 passi (Timed 25-Foot Walk, T25FW), il test dei nove pioli (9 Hole Peg Test, 9HPT) e il test delle addizioni sequenziali (Paced Auditory Serial Addition Test, PASAT) in 3 secondi.
    Il miglioramento della funzione neuro-fisica e/o cognitiva viene definito da almeno 1 dei seguenti aspetti:
    Una diminuzione di ≥1.0 punti del valore EDSS rispetto al punteggio baseline di ≤6.0 (diminuzione costante per 3 mesi o più).
    Un miglioramento ≥15% dalla baseline nel T25FW (miglioramento costante per 3 mesi o più).
    Un miglioramento ≥15% dalla baseline nel 9HPT (miglioramento costante per 3 mesi o più).
    Un miglioramento ≥15% dalla baseline nel PASAT (miglioramento costante per 3 mesi o più).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Quarterly over 72 weeks
    Ogni 3 mesi durante le 72 settimane di trattamento.
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints:
    Percentage of subjects experiencing confirmed worsening of
    neurophysical
    and/or cognitive function and/or disability over 72 weeks
    (approximately 18 months) of treatment as measured by a composite
    endpoint of the EDSS, T25FW, 9HPT, and PASAT.
    Progression of disability or worsening of neuro-physical and/or cognitive
    function is defined as at least 1 of the following: A ≥1.0 point increase in
    EDSS from a baseline score of ≤5.5 or a ≥0.5 point increase from a
    baseline score equal to 6.0 (increase sustained for 3 months orgreater).
    A ≥15% worsening from baseline in T25FW (worsening sustained for 3
    months or greater). A ≥15% worsening from baseline in 9HPT
    (worsening sustained for 3 months or greater). A ≥15% worsening from
    baseline in PASAT (worsening sustained for 3 months or greater).Safety Endpoints
    The following safety parameters will be used to address the safety and
    tolerability portion of the secondary objectives: Adverse events (AEs)
    Serious adverse events (SAEs) Clinical laboratory test results Physical
    examination findings Electrocardiogram (ECG) Vital signs results Weight
    Serum antibodies (Ab) to BIIB033 Disease activity by brain MRI metrics
    MS signs and symptoms Columbia Suicide Severity Rating Scale (C-SSRS)
    score
    Pharmacokinetic Endpoint
    The PK portion of the secondary objectives will be addressed by the
    following: BIIB033 population PK assessment
    End point secondari di Efficacia
    Percentuale di soggetti con peggioramento confermato della funzionalità neuro-fisica e/o cognitiva e/o disabilità nell'arco di 72 settimane (circa 18 mesi) di trattamento misurato tramite endpoint composito, dato da EDSS, T25FW, 9HPT e PASAT.
    La progressione della disabilità o il peggioramento della funzione neuro-fisica e/o cognitiva viene definita/o da almeno 1 dei seguenti aspetti:
    Un aumento di ≥1.0 punti del valore EDSS rispetto al punteggio baseline ≤5.5 punti o un aumento ≥0.5 punti rispetto al punteggio baseline pari a 6.0 (aumento costante per 3 mesi o più).
    Un peggioramento ≥15% dalla baseline nel T25FW (peggioramento costante per 3 mesi o più).
    Un peggioramento ≥15% dalla baseline nel 9HPT (peggioramento costante per 3 mesi o più).
    Un peggioramento ≥15% dalla baseline nel PASAT (peggioramento costante per 3 mesi o più).
    Endpoint di sicurezza
    I seguenti parametri relativi alla sicurezza saranno impiegati per affrontare la parte relativa alla sicurezza ed alla tollerabilità degli obiettivi secondari:
    Eventi avversi (AE)
    Eventi avversi gravi (SAE)
    Risultati dei test clinici di laboratorio
    Risultati dell'esame fisico
    Elettrocardiogramma (ECG)
    Risultati dei segni vitali
    Peso
    Anticorpi nel siero (Ab) per BIIB033
    Attività della malattia tramite metriche della RM cerebrale
    Segni e sintomi della sclerosi multipla
    Punteggio secondo la scala Columbia Suicide Severity Rating Scale (C-SSRS)
    Endpoint di farmacocinetica
    La parte di farmacocinetica degli obiettivi secondari sarà affrontata considerando i seguenti elementi: Valutazione della farmacocinetica di popolazione per BIIB033
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy Assessments: Quarterly over 72 weeks
    Safety Assessments and PK/PD Sampling: at specified timepoints during
    the treatment period (day 1 to week 72) and follow up period (through
    EOS ~week 84)
    Valutazione di efficacia: Ogni 3 mesi durante le 72 settimane di trattamento.
    Valutazione della sicurezza e collezione campioni PK/PD: ad ogni specifico timepoint durante il periodo di trattamento (dal giorno 1 alla settimana 72) e nel periodo di follow up (fino all’ultima visita, alla settimana 84 circa).
    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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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.8.2.4Number of treatment arms in the trial5
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    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
    Canada
    Russian Federation
    Serbia
    United States
    E.8.7Trial has a data monitoring committee No
    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
    Ultima visita dell'ultimo paziente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months10
    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 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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 396
    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 state72
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 339
    F.4.2.2In the whole clinical trial 396
    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)
    Standard of care; no further provisions are made for access to the study treatments beyond the protocol-specified treatment duration.
    Terapia standard. Nessuna possibilità di accesso al farmaco in studio al di la della durata del trattamento specificata nel protocollo.
    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 Decision2013-06-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-05-23
    P. End of Trial
    P.End of Trial StatusOngoing
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