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    Summary
    EudraCT Number:2011-006262-40
    Sponsor's Protocol Code Number:215MS201
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-06-13
    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 ConcernedSpain - AEMPS
    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®
    Estudio aleatorizado, doble ciego, controlado con placebo, en grupos paralelos y de búsqueda de dosis para evaluar la eficacia, la seguridad, la tolerabilidad y la farmacocinética de BIIB033 en pacientes con formas recidivantes de esclerosis múltiple cuando se utiliza simultáneamente 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®
    Un estudio para evaluar la seguridad y la eficacia de BIIB033 en pacientes con formas recidivantes de esclerosis múltiple cuando se emplea de forma conjunta con 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.3.8INN - Proposed INNNo disponible
    D.3.9.2Current sponsor codeBIIB033
    D.3.9.3Other descriptive nameAnticuerpo monoclonal anti-LINGO-1 humano
    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 AuthorisationSpain
    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.3.9.1CAS number 145258-61-3
    D.3.9.3Other descriptive nameINTERFERON 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
    Formas recidivantes de esclerosis múltiple
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis
    Esclerosis múltiple
    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.
    El objetivo principal del estudio es evaluar la eficacia de BIIB033 en pacientes con EM recidivante activa cuando se utiliza simultáneamente 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.
    Los objetivos secundarios de este estudio en esta población en estudio son valorar la seguridad, la tolerabilidad y la FC poblacional de BIIB033 cuando se administra simultáneamente 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.
    Subestudio opcional de punción lumbar: Se recogerá LCR para valorar la modulación de posibles biomarcadores FD o de otro tipo que puedan guardar relación con la actividad de BIIB033 o la actividad de la enfermedad de la EM.
    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. Capacidad de comprender el objetivo y los riesgos del estudio y de dar el consentimiento informado firmando y fechando el impreso de consentimiento informado (ICI) y la autorización de uso de la información sanitaria confidencial de conformidad con las normas nacionales y locales relativas a la intimidad de los pacientes.
    2. Edad de 18 a 58 años, ambas inclusive, en el momento del consentimiento informado.
    3. Diagnóstico de EMRR según los criterios de McDonald de 2005 o de comienzo de EMPS según los criterios de Lublin y Reingold.
    4. En el caso de la EMRR, los pacientes deberán tener actividad de la enfermedad, definida como dos o más episodios diferenciados de cualquiera de los 3 siguientes en los 12 meses previos al reclutamiento:
    ? Recidiva clínica.
    ? Lesión Gd+ en la RM (RM cerebral o medular)
    ? Lesión en T2 nueva en la RM (RM cerebral o medular)
    5. En el caso de la EMPS, los pacientes deberán tener actividad de la enfermedad, definida como 1 o más episodios diferenciados de cualquiera de las 2 siguientes en los 12 meses previos al reclutamiento:
    ? Recidiva clínica.
    ? Lesión Gd+ en la RM (RM cerebral o medular)
    6. Puntuación basal de la EDSS de 2 a 6.
    7. Todos los pacientes varones y las mujeres en edad fértil deberán utilizar un método anticonceptivo eficaz durante el estudio y estar dispuestos a continuar su uso durante al menos 6 meses después de la última dosis del tratamiento del estudio (BIIB033 y Avonex o placebo y 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 Beta preparation (e.g., Avonex, Rebif, interferon Beta-1b, or any generic interferon Beta). (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 Beta)
    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 Beta.
    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.
    1. Antecedentes de anomalías analíticas que, en opinión del investigador, indiquen cualquier enfermedad cardíaca, endocrina, hematológica, inmunológica, metabólica, urológica, pulmonar, digestiva, dermatológica, psiquiátrica, renal, neurológica (excepto EM) importante u otra enfermedad grave que impida la administración de BIIB033 o de Avonex.
    2. Cualquiera de las anomalías analíticas siguientes en la selección:
    ? hemoglobina <= 9,0 g/dl
    ? recuento de plaquetas <= 100 X 109/l
    ? linfocitos <= 1,0 X 109/l
    ? neutrófilos <= 1,5 X 109/l
    ? alanina aminotransferasa/transaminasa glutamicopirúvica sérica (ALT/SGPT), aspartato aminotransferasa/transaminasa glutamicooxaloacética sérica (AST/SGOT) o gammaglutamiltransferasa >= 2 veces el límite superior normal (LSN)
    ? creatinina sérica >= LSN.
    3. Tratamiento con Botox para la espasticidad de las extremidades en los 6 meses previos al día 1/momento basal.
    4. Planes para someterse a procedimientos/intervenciones de cirugía mayor programados en cualquier momento durante el estudio.
    5. Participación simultánea en otro protocolo de estudio.
    6. Tratamiento con cualquier fármaco para la EM en investigación en las 3 semanas o 5 t1/2 (lo que sea más largo) antes del día 1/momento basal.
    7. Tratamiento con dosis altas de esteroides orales o IV <= 30 días antes del día 1/momento basal.
    8. Antecedentes de ideas suicidas o de un episodio de depresión clínicamente grave (determinados por el investigador) en los 3 meses previos al reclutamiento. Nota: los pacientes que estén recibiendo tratamiento antidepresivo no se excluirán del estudio a menos que se haya aumentado la medicación en los 6 meses previos al reclutamiento.
    9.Los pacientes con EMRR que tengan antecedentes de respuesta insuficiente a cualquier preparado de interferón Beta aprobado (en su país de residencia) (p. ej., Avonex, Rebif, interferón Beta-1b o cualquier interferón Beta genérico). (Definición de respuesta insuficiente: 2 o más episodios diferenciados de recidiva clínica o lesión Gd+ en la RM o lesión nueva o sin realce en la RM en cualquier período de 12 meses mientras se cumple el tratamiento con interferón Beta.)
    10. Antecedentes del virus de la inmunodeficiencia humana o de otros procesos inmunodeficientes.
    11. Antecedentes de resultado positivo de la prueba del Ac del virus de la hepatitis C o del virus de la hepatitis B (definida como positiva para el antígeno de superficie de la hepatitis B o para el Ac nuclear de la hepatitis B).
    12.Antecedentes de toxicomanías o alcoholismo (a criterio del investigador) en los dos años previos a la aleatorización.
    13.Antecedentes de trastorno convulsivo o desmayos inexplicados O antecedentes de una crisis convulsiva en los 6 meses previos al momento basal.
    14. Mujeres con una prueba de embarazo positiva, embarazadas o que están amamantando.
    15. T25FW >30 segundos (en cualquier de las 2 pruebas en la selección).
    16. Antecedentes de procesos malignos; no obstante, los pacientes con antecedentes de carcinoma basocelular tratados o extirpados o menos de 3 carcinomas epidermoides son elegibles para participar en este estudio.
    17. Disfunción renal con un aclaramiento de creatinina <80 ml/min en la selección (aclaramiento de creatinina calculado con la ecuación de Cockcroft-Gault).
    18. En opinión del investigador, antecedentes de Ac neutralizantes persistentes y de importancia clínica contra el interferón Beta.
    19. Intolerancia conocida o contraindicación de Avonex, o antecedentes de incumplimiento con Avonex.
    20.Tratamiento con fingolimod o agonistas del receptor 1 de esfingosina 1-fosfato (S1P1) en investigación en los 3 meses previos al día 1/momento basal.
    21.Tratamiento con natalizumab en los 3 meses previos al día 1/momento basal.
    22.Inicio del tratamiento o ajuste de la dosis de 4-aminopiridina (4-AP) o productos relacionados comercializados en los últimos 28 días. Nota: no se excluirá a los pacientes que hayan recibido una dosis estable de 4-AP comercializada durante más de 28 días.
    23.Tratamiento con cualquier fármaco quimioterápico (p. ej., mitoxantrona, ciclofosfamida, cladribina) o Acm depletores de células (p. ej., rituximab, ocrelizumab, alemtuzumab) en los 6 meses previos al día 1/momento basal, a menos que el tratamiento con el fármaco quimioterápico/Acm depletores de células se produzca antes de los 3 meses anteriores al día 1/momento basal (es decir, entre los meses 3 y 6 anteriores al día 1/momento basal) y el recuento de leucocitos del paciente esté dentro del intervalo normal en la selección.
    24. Una recidiva de la EM ocurrida en los 90 días previos al día 1/momento basal o el sujeto no se ha estabilizado después de una recidiva previa antes de la selección.
    25.Incapacidad para cumplir los requisitos del estudio.
    26.Otro motivo no especificado que, en opinión del investigador o de Biogen Idec, impida el reclutamiento del paciente.
    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).
    Criterio de valoración de la eficacia principal:
    Porcentaje de sujetos que experimentan mejoría confirmada de la función neurofísica o cognitiva durante 72 semanas (aprox. 18 meses) de tratamiento, determinada por un criterio de valoración compuesto formado por la Escala ampliada del estado de discapacidad (EDSS), la marcha cronometrada de 25 pies (T25FW), la prueba del tablero con 9 agujeros (9HPT) y la prueba de adición auditiva secuencial pautada (3 segundos) (PASAT).
    La mejoría de la función neurofísica o cognitiva se define como al menos 1 de los siguientes: Un descenso >=1,0 puntos en la EDSS desde una puntuación basal <=6,0 (descenso sostenido durante 3 o más meses). Una mejoría >= 15 % en la T25FW respecto al valor basal (mejoría sostenida durante 3 o más meses). Una mejoría >= 15 % en la 9HPT respecto al valor basal (mejoría sostenida durante 3 o más meses). Una mejoría >= 15 % en la PASAT respecto al valor basal (mejoría sostenida durante 3 o más meses).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Quarterly over 72 weeks
    Cada tres meses durante 72 semanas
    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
    Criterios de valoración de la eficacia secundarios:
    Porcentaje de pacientes que sufren empeoramiento confirmado de la función neurofísica o cognitiva o discapacidad durante 72 semanas (alrededor de 18 meses) de tratamiento, medido por un criterio de valoración compuesto de la EDSS, la T25FW, la 9HPT y la PASAT.
    La progresión de la discapacidad o el empeoramiento de la función neurofísica o cognitiva se definen como al menos 1 de los siguientes: Un aumento de >= 1,0 puntos en la EDSS desde una puntuación basal de <= 5,5 o un aumento de >= 0,5 puntos respecto a una puntuación basal igual a 6,0 (aumento mantenido durante 3 o más meses). Un empeoramiento >= 15 % en la T25FW respecto al valor basal (empeoramiento sostenido durante 3 o más meses). Un empeoramiento >= 15 % en la 9HPT respecto al valor basal (empeoramiento sostenido durante 3 o más meses). Un empeoramiento >= 15 % en la PASAT respecto al valor basal (empeoramiento sostenido durante 3 o más meses).
    Criterios de valoración de la seguridad
    Se utilizarán los parámetros de seguridad siguientes para abordar el apartado de seguridad y tolerabilidad de los objetivos secundarios: Acontecimientos adversos (AA) y acontecimientos adversos graves (AAG), resultados analíticos, hallazgos de la exploración física, electrocardiograma (ECG), resultados de las constantes vitales, peso, anticuerpos (Ac) séricos contra BIIB033, actividad de la enfermedad por métodos de medición de la RM cerebral, signos y síntomas de EM y puntuación de la Escala de Columbia de valoración de la intensidad de la tendencia suicida de Columbia (C-SSRS).
    Criterio de valoración farmacocinético
    La parte FC de los objetivos secundarios se basará en: La valoración de la FC poblacional de 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)
    Valoraciones de eficacia: Cada tres meses durante 72 semanas
    Valoraciones de seguridad y muestreo de FC/FD: en los momentos especificados durante el periodo de tratamiento (día 1 a la semana 72) y periodo de seguimiento (a lo largo del final del estudio ~ semana 84)
    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 concerned9
    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
    Czech Republic
    France
    Hungary
    Italy
    Netherlands
    Poland
    Russian Federation
    Serbia
    Spain
    United Kingdom
    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
    UVUP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    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 years2
    E.8.9.2In all countries concerned by the trial months11
    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 state30
    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.
    Cuidado habitual: no existen previsiones de acceso a los tratamientos del estudio una vez cubierta la duración del tratamiento indicada en el protocolo.
    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 Decision2013-06-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-06-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-03-29
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