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    Summary
    EudraCT Number:2013-004622-29
    Sponsor's Protocol Code Number:101MS408
    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:2014-10-03
    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 number2013-004622-29
    A.3Full title of the trial
    A Multicenter, Randomized, Open-Label Study to Assess the Impact of Natalizumab versus Fingolimod on Central Nervous System Tissue Damage and Recovery in Active Relapsing-Remitting Multiple Sclerosis Subjects
    Estudio abierto, multicéntrico, aleatorizado para evaluar el impacto de natalizumab frente a fingolimod en lesiones del tejido del sistema nervioso central y en la recuperación de sujetos con esclerosis múltiple recidivante-remitente activa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Impact of Natalizumab versus Fingolimod on Central Nervous System (CNS) Tissue Damage and Recovery in Active Relapsing-Remitting Multiple Sclerosis (RRMS) Subjects
    Impacto de natalizumab frente a fingolimod en lesiones del tejido del sistema nervioso central y en la recuperación de sujetos con esclerosis múltiple recidivante-remitente activa
    A.4.1Sponsor's protocol code number101MS408
    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.4.1Name of organisation providing supportBiogen Idec MA Inc.
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportBiogen Idec Australia Pty Ltd
    B.4.2CountryAustralia
    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 pointAna Asenjo
    B.5.3 Address:
    B.5.3.1Street AddressPaseo de la Castellana, 41
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28046
    B.5.3.4CountrySpain
    B.5.4Telephone number34913107161
    B.5.5Fax number34913107111
    B.5.6E-mailana.asenjo@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 Yes
    D.2.1.1.1Trade name Tysabri®
    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 nameAN100226, BG00002
    D.3.4Pharmaceutical form Concentrate and solvent for 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 INNNATALIZUMAB
    D.3.9.1CAS number 189261-10-7
    D.3.9.4EV Substance CodeSUB22282
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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 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 Gilenya
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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 nameFingolimod
    D.3.4Pharmaceutical form 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 INNfingolimod
    D.3.9.1CAS number 162359-56-0
    D.3.9.3Other descriptive nameFINGOLIMOD HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB30967
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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.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
    Multiple Sclerosis (MS)
    Esclerosis Múltiple (EM)
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis (MS)
    Esclerosis Múltiple (EM)
    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 17.0
    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 assess the effect of natalizumab compared to fingolimod on the evolution of
    new on-treatment T1-gadolinium-enhancing (Gd+) lesions to persistent black holes (PBH) over 52 weeks.
    El objetivo principal del estudio es evaluar el impacto de natalizumab en comparación con fingolimod en la evolución de lesiones potenciadas con gadolinio (Gd+) en T1 nuevas en tratamiento que evolucionan a agujeros negros persistentes (PBH) durante 52 semanas.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to assess the effect of natalizumab compared to fingolimod on:
    ? MRI measures of CNS tissue destruction as measured by the number of new T1-Gd+ lesions.
    ? Various other MRI measures of disease activity.
    ? No Evidence of Disease Activity (NEDA)
    ? Relapse on treatment over 52 weeks.
    ? The change in information processing speed as measured by the Symbol Digit Modalities Test (SDMT).
    Los objetivos secundarios de este estudio son evaluar el impacto de natalizumab en comparación con fingolimod en cuanto a:
    ? Medidas de RMN de la destrucción del tejido del SNC según el número de lesiones Gd+ en T1 nuevas.
    ? Otras medidas de RMN de la actividad de la enfermedad.
    ? Ausencia de evidencia de actividad de la enfermedad (NEDA).
    ? Recidiva con tratamiento durante 52 semanas.
    ? El cambio en la velocidad de procesamiento de la información según la prueba de símbolos y dígitos (SDMT).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The Diffusion Tensor Imaging (DTI) substudy, the structural changes in brain tissue within lesions and normal appearing white matter (NAWM) by measuring through voxel-wise analysis the extent and severity of fractional anisotrophy (FA)- and diffusivity-measured tissue damage of natalizumab- and fingolimodtreated subjects over 52 weeks compared to healthy volunteer cohort.
    El subestudio de imágenes con tensor de difusión (DTI), evaluar los cambios estructurales del tejido cerebral en las lesiones y la sustancia blanca de apariencia normal (NAWM) mediante análisis basados en vóxel para determinar el alcance y la intensidad del daño del tejido calculado mediante anisotropía fraccional (AF) y difusividad en sujetos tratados con natalizumab y fingolimod durante 52 semanas en comparación con una cohorte de voluntarios sanos.
    E.3Principal inclusion criteria
    Inclusion Criteria for MS Patients:
    - Must have a documented diagnosis of relapsing MS (McDonald 2010 Criteria [Polman 2011]) at study screening.
    - If the subject is on BRACE at study screening:
    ? He/she must have been on therapy for at least 12 months, and
    ? Experienced ?1 relapse within the last 6 months prior to study screening with ?1 new T1-Gd+ lesion or ?2 new T2 lesions on a brain MRI scan performed ?6 months prior to study screening, with comparison made to a T2 MRI scan performed up to 18 months before study screening.
    - If the subject is DMT naïve at study screening, he/she must have experienced ?2 relapses in the 12 months prior to study screening. In addition, they must have had ?1 new T1-Gd+ lesion or ?2 new T2 lesions on a brain MRI scan performed ?6 months prior to study screening, with comparison made to a T2 MRI scan performed up to 18 months
    prior to study screening.
    - Willing to take natalizumab or fingolimod as the only DMTs for the duration of the study.
    - Must have an EDSS score from 0 to 5.5 inclusive at study screening.

    Inclusion Criteria for Healthy Volunteers:
    - Subjects who are generally healthy as demonstrated by physical examination and by medical history, with no history or evidence of major illnesses, diseases, or disorders.
    - Subjects of childbearing potential must practice effective contraception and be willing and able to continue contraception for duration of the study.
    - History of drug or alcohol abuse (as defined by the Investigator) within 1 year prior to study screening.
    - Willing and able to comply with scheduled visits and imaging services.

    NOTE: Other protocol defined Inclusion criteria may apply
    Criterios de inclusión para pacientes con ES:
    - Diagnóstico confirmado de EM recidivante (criterios de McDonald 2010 [Polman 2011]) en la selección del estudio.
    - Si el sujeto recibe BRACE en la selección del estudio:
    ? Debe haber recibido tratamiento durante 12 meses como mínimo.
    ? Debe haber sufrido ?1 recidiva en los últimos 6 meses antes de la selección del estudio con ?1 lesión Gd+ en T1 nueva o ?2 lesiones en T2 nuevas confirmadas mediante una RMN cerebral en los ?6 meses anteriores a la selección del estudio, en comparación con una RMN en T2 realizada en los 18 meses anteriores a la selección del estudio.
    - Si el sujeto no ha recibido tratamiento con TME en la selección del estudio, debe haber sufrido ?2 recidivas en los 12 meses anteriores a la selección del estudio. Además, deben haber tenido ?1 lesión Gd+ en T1 nueva o ?2 lesiones en T2 nuevas confirmadas mediante una RMN cerebral realizada en los ?6 meses anteriores a la selección del estudio, en comparación con una RMN en T2 realizada en los 18 meses anteriores a la selección del estudio como máximo.
    - Disposición a tomar natalizumab o fingolimod como TME único durante el estudio.
    - Puntuación de EDSS de 0 a 5,5, ambos incluidos, en la selección del estudio.
    Criterios de inclusión para pacientes sanos:
    - Sujetos generalmente sanos de acuerdo con las exploraciones físicas y el historial médico, sin antecedentes o indicios de enfermedades, afecciones o trastornos graves.
    - Los sujetos en edad fértil deben tomar medidas anticonceptivas eficaces y estar dispuestos y ser capaces de continuar con estas durante el estudio.
    - Antecedentes de abuso de drogas o alcohol (según lo determine el investigador) en el año anterior a la selección del estudio.
    - Capacidad y disposición de cumplir con las visitas y los servicios de diagnóstico por imagen programados.
    NOTA: Pueden aplicar otros criterios de inclusión definidos en el protocolo.
    E.4Principal exclusion criteria
    Exclusion Criteria for MS Patients:
    - History of or positive test result at study screening for human immunodeficiency virus (HIV).
    - History or positive test result at study screening for hepatitis C virus (HCV) antibody or current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/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 immunoglobulin G, and positive HBcAb) are eligible to participate in the study (definitions are based on the United States (US) Centers for Disease Control and Prevention [CDC]?s interpretation of the hepatitis B serology panel).
    - Prior treatment with natalizumab or fingolimod
    - Diagnosis of Primary Progressive Multiple Sclerosis [PPMS] and/or Secondary Progressive Multiple Sclerosis [SPMS]
    - History of or known active malignant disease, including solid tumors and hematologic malignancies (subjects with cutaneous basal and squamous cell carcinoma that has been completely excised and considered cured prior to study screening remain eligible).
    - History of opportunistic infections (including PML) or any clinically significant cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic (other than MS), dermatologic, psychiatric, and renal condition, or other major disease, as determined by the Investigator.
    - A clinically significant infectious illness (e.g., pneumonia, septicemia) within the 1 month prior to study screening
    - History of drug or alcohol abuse (as defined by the Investigator) within 1 year prior to study screening
    - Exposure to intravenous immunoglobulin (IVIg), monoclonal antibodies, cytokines, growth factors, soluble receptors, other recombinant products, or fusion proteins within one year prior to study screening.
    - Prior history of immunosuppressant use (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate, cladribine, rituximab) in the last 12 months prior to study screening. Treatment with IV and/or oral corticosteroids (topical corticosteroids are acceptable) within three weeks of baseline DTI-MRI assessment.
    - An MS relapse that has occurred within the 30 days prior to randomization and/or the subject has not stabilized from a previous relapse prior to randomization.
    - Current/previous participation in investigational drug studies within 90 days prior to study screening or 5 times the compound?s half-life, whichever is longer.
    - History or evidence of macular edema on ophthalmologic exam.
    - History of myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure in last 6 months.
    - Mobitz type II second degree or third degree AV block or sick sinus syndrome, symptomatic bradycardia, recurrent syncope, or severe untreated sleep apnea.
    - Baseline corrected QTc (Fridericia [QTcF] or Bazett?s [QTcB] formula) interval ?470 ms in females and ?450 ms in males.
    - Treatment with Class Ia (e.g., procainamide, quinidine, ajmaline, disopyramide) or Class III (amiodarone, bretylium, dofelitide, sotalol, ibulitide, azilimide) anti-arrhythmic drugs.
    - Concurrent therapy with drugs that slow heart rate (e.g., beta-blockers, heart-rate lowering calcium channel blockers such as diltiazem or verapamil, or digoxin).
    - Hypertension not controlled with prescribed medications.
    - History of severe respiratory disease, pulmonary fibrosis or class III or IV chronic obstructive pulmonary disease.
    - Subjects without immunity to varicella zoster virus (VZV) from either active vaccination or from previous natural infection (defined as negative IgG antibodies) at study screening.
    - The use of live or live attenuated vaccination within 8 weeks of study screening.
    - Presence of a metal device affected by MRI (e.g., any type of electronic, mechanical or magnetic implant, cardiac pacemaker, aneurysm clips, implanted cardiac defibrillator) or potential ferromagnetic foreign body (metal slivers, metal shavings, other metal objects), which would be a contraindication for MRI
    - Claustrophobia sufficient to interfere with generating reliable MRI scans in MS subjects in the DTI sub-study
    Exclusion Criteria for Healthy Volunteers:
    - Claustrophobia sufficient to interfere with generating reliable MRI scans
    - History of other major illness including neurological disorders as determined by the Investigator
    - Presence of a metal device affected by MRI (e.g., any type of electronic, mechanical or magnetic implant, cardiac pacemaker, aneurysm clips, implanted cardiac defibrillator) or potential ferromagnetic foreign body (metal slivers, metal shavings, other metal objects), which would be a contraindication for MRI

    NOTE: Other protocol defined Exclusion criteria may apply
    Criterios de exclusión para pacientes con EM:
    - Antecedentes del virus de la inmunodeficiencia humana (VIH), o detección positiva para esta prueba, en la selección.
    - Antecedentes del anticuerpo del virus de la hepatitis C (HCV, infección por hepatitis B actual (definida como detección positiva para el antígeno de superficie de la hepatitis B [HBsAg] o el antígeno nuclear del virus de la hepatitis B [HBcAb]), o detección positiva para estas pruebas, en la selección. Los sujetos con inmunidad a la hepatitis B ya sea por vacunación activa (definida como detección negativa para HBsAg, positiva para el antígeno de superficie de la hepatitis B [HBsAb] y negativa para HBcAb) o bien por infección natural previa (definida como detección negativa para HBsAg, positiva para inmunoglobulina G HBsAb y positiva para HBcAb) son aptos para participar en el estudio (las definiciones se basan en la interpretación de los Centros para la Prevención y el Control de Enfermedades (Centers for Disease Control and Prevention, CDC) de los Estados Unidos de la serología de la hepatitis B).
    - Tratamiento anterior con natalizumab o fingolimod.
    - Diagnóstico de esclerosis múltiple primaria progresiva (EMPP) o esclerosis múltiple secundaria progresiva (EMSP).
    - Antecedentes o conocimiento de una enfermedad maligna activa, incluidos tumores sólidos y neoplasias hematológicas malignas (los sujetos con carcinoma basocelular o espinocelular extirpado completamente y que se considera curado antes de la selección del estudio seguirán siendo aptos para el estudio).
    - Antecedentes de infecciones oportunistas (incluida la LMP) o cualquier enfermedad clínicamente significativa cardíaca, endocrina, hematológica, hepática, inmunitaria, metabólica, urológica, pulmonar, neurológica (excepto la EMRR), dermatológica, psiquiátrica, renal u otra enfermedad importante, según lo determine el investigador.
    - Una enfermedad infecciosa clínicamente significativa (p. ej. neumonía o septicemia) en el mes previo a la selección.
    - Antecedentes de abuso de drogas o alcohol (según lo determine el investigador) en el año anterior a la selección del estudio.
    - Exposición a inmunoglobulina intravenosa (IgIV), anticuerpos monoclonales, citocinas, factores de crecimiento, receptores solubles, otros productos recombinantes o proteínas de fusión en el año anterior a la selección del estudio.
    - Antecedentes de uso de inmunodepresores (p. ej., mitoxantrona, azatioprina, metotrexato, ciclofosfamida, micofenolato, cladribina o rituximab) en los 12 meses anteriores a la selección del estudio. El tratamiento con corticoesteroides IV y/u orales (se aceptan corticoesteroides tópicos) en los tres meses anteriores a la evaluación de DTI por RMN inicial.
    - Una recidiva de la EM que haya tenido lugar en los 30 días anteriores a la aleatorización; o bien, el sujeto no se ha estabilizado desde una recidiva anterior previa a la aleatorización.
    - Participación actual o previa en estudios de fármacos en investigación en los 90 días anteriores a la selección del estudio o 5 veces la semivida el compuesto, lo que tenga mayor duración.
    - Antecedentes o indicios de edema macular en la evaluación oftalmológica.
    - Antecedentes de infarto de miocardio, angina inestable, accidente cerebrovascular, accidente isquémico transitorio o insuficiencia cardíaca descompensada en los últimos 6 meses.
    - Bloqueo AV de segundo o tercer grado tipo Mobitz II o síndrome del seno enfermo, bradicardia sintomática, síncope recurrente o apnea del sueño grave no tratada.
    - Intervalo QTc corregido inicial (fórmula de Fridericia [QTcF] o de Bazett [QTcB]) ?470 ms en mujeres y ?450 ms en varones.
    - Tratamiento con antiarrítmicos de clase Ia (p. ej., procainamida, quinidina, ajmalina, disopiramida) o de clase III (amiodarona, bretilio, dofelitide, sotalol, ibulitide o azilimide).
    - Tratamiento actual con fármacos que ralentizan la frecuencia cardíaca (p. ej., betabloqueantes, bloqueadores de los canales de calcio que ralentizan la frecuencia cardíaca, tales como diltiazem, verapamilo o digoxina).
    - Hipertensión no controlada con medicamentos con receta.
    NOTA: Véase otros criterios de exclusión en el protocolo
    Criterios de exclusión para pacientes sanos:
    - Un nivel de claustrofobia que no permita generar imágenes fiables por RMN.
    - Antecedentes de otras enfermedades graves como trastornos neurológicos, según lo determine el investigador.
    - Presencia de un dispositivo de metal que se pueda ver afectado por una RMN (p. ej., cualquier tipo de implante magnético, mecánico o electrónico, marcapasos, grapas de aneurisma o desfibrilador automático implantable) o cuerpos extraños posiblemente ferromagnéticos (astillas o fragmentos de metal u otros objetos de metal) que podrían ser contraindicaciones para las RMN
    NOTA: Véase otros criterios de exclusión en el protocolo
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is the cumulative number of ?6-month confirmed T1-hypointense lesions (i.e., PBH) arising from new on-treatment T1-Gd+ lesions.
    El criterio de valoración principal del estudio es el número acumulado de lesiones hipointensas en T1 confirmadas durante ?6 meses (p. ej., PBH) resultantes de lesiones Gd+ en T1 nuevas en tratamiento
    E.5.1.1Timepoint(s) of evaluation of this end point
    Weeks 4, 8, 12, 16, 20, 24, 52
    Semanas 4, 8, 12, 16, 20, 24, 52
    E.5.2Secondary end point(s)
    The secondary endpoints of this study are the follwoing:
    ? MRI endpoints:
    o Cumulative number of new T1-Gd+ lesions .
    o Change in total T1-hypointense and total T2-hyperintense lesion volumes.
    o Cumulative number of new or enlarging T2 lesions.
    ? Proportion of subjects with NEDA according to the following definition:
    o No relapses.
    o No 12-week confirmed disability progression based on EDSS.*
    o No new T1-Gd+ lesions on brain MRI.
    o No new or enlarging T2-hyperintense lesions.
    ? Time to first relapse, cumulative risk of relapses and time to complete recovery from first relapse. **
    ? Change in information processing speed as measured by the SDMT from baseline to Week 24 and Week 52.

    * Increase of 1.0 or more on the EDSS from a baseline score of 1.0 or more, or an increase of 1.5 or more from a baseline score of 0 that was sustained for 12 weeks (progression could not be confirmed during a relapse).
    ** 12-week confirmed complete Expanded Disability Status Scale (EDSS) recovery from first on-treatment relapse is defined as an EDSS score that is equal to or lower than the last pre-relapse EDSS score and sustained for at least 12 week
    Los criterios de valoración secondarios del estudio son los siguientes:
    ? Criterios de valoración de las RMN:
    o Número acumulado de lesiones Gd+ en T1 nuevas.
    o Cambio en los volúmenes totales de las lesiones hipointensas en T1 e hiperintensas en T2.
    o Número acumulado de lesiones en T2 nuevas o aumentadas.
    ? Proporción de sujetos con NEDA según los parámetros siguientes:
    o Sin recidivas.
    o Sin progresión de la discapacidad de 12 semanas confirmada según la EDSS.*
    o Ausencia de lesiones Gd+ en T1 nuevas en las RMN cerebrales.
    o Ausencia de lesiones hiperintensas en T2 nuevas o aumentadas.
    ? Tiempo hasta la primera recidiva, riesgo acumulado de recidivas y tiempo hasta la recuperación completa de la primera recidiva. **
    ? Cambio en la velocidad de procesamiento de la información según el SDMT desde el inicio hasta la semana 24 y la semana 52
    * Aumento de 1,0 puntos o más en la EDSS en una puntuación inicial de 1,0 o más, o aumento de 1,5 puntos o más en una puntuación inicial de 0 que se ha mantenido durante 12 semanas (la progresión no se ha podido confirmar durante una recidiva).
    ** Una recuperación completa de 12 semanas confirmada por la Escala ampliada del estado de discapacidad (EDSS) desde la primera recidiva con tratamiento se define como una puntuación en la EDSS igual o inferior que la última puntuación en la EDSS anterior a la recidiva que se han mantenido durante al menos 12 semanas.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Weeks 4, 8, 12, 16, 20, 24, 52
    Semanas 4, 8, 12, 16, 20, 24, 52
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 concerned10
    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
    Australia
    Canada
    Czech Republic
    Denmark
    France
    Germany
    Italy
    Spain
    Sweden
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months7
    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: 540
    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 Yes
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 327
    F.4.2.2In the whole clinical trial 540
    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)
    None
    Ninguna
    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 Decision2014-12-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-06-17
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