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    Summary
    EudraCT Number:2020-005929-89
    Sponsor's Protocol Code Number:CLOU064C12302
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-12-22
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2020-005929-89
    A.3Full title of the trial
    A randomized, double-blind, double-dummy, parallel-group study,
    comparing the efficacy and safety of remibrutinib versus teriflunomide in participants with relapsing multiple sclerosis, followed by extended treatment with open-label remibrutinib
    Estudio aleatorizado, doble ciego con doble enmascaramiento y grupos paralelos en el que se compara la eficacia y seguridad de remibrutinib frente a teriflunomida en participantes con esclerosis múltiple recurrente, seguido de una extensión abierta del tratamiento con remibrutinib
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of remibrutinib compared to teriflunomide in participants with relapsing multiple sclerosis, followed by long term treatment with remibrutinib
    Eficacia y seguridad de remibrutinib comparado con teriflunomida en participantes con esclerosis múltiple recurrente, seguido de tratamiento a largo plazo con
    remibrutinib
    A.4.1Sponsor's protocol code numberCLOU064C12302
    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 SponsorNovartis Farmacéutica S.A.
    B.1.3.4CountrySpain
    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 supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmacéutica S.A.
    B.5.2Functional name of contact pointTrial Monitoring Organization (TMO)
    B.5.3 Address:
    B.5.3.1Street AddressGran vía de les Corts Catalanes, 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number+3493 0353036
    B.5.5Fax number+3493 2479903
    B.5.6E-maileecc.novartis@novartis.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 nameremibrutinib
    D.3.2Product code LOU064
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNRemibrutinib
    D.3.9.2Current sponsor codeLOU064C
    D.3.9.4EV Substance CodeSUB204118
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Aubagio
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi-Aventis Groupe
    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 nameTeriflunomide
    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 INNTeriflunomide
    D.3.9.1CAS number 108605-62-5
    D.3.9.4EV Substance CodeSUB25218
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number14
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Multiple Sclerosis
    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 21.0
    E.1.2Level PT
    E.1.2Classification code 10080700
    E.1.2Term Relapsing 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
    Core part:
    Demonstrate that remibrutinib is superior to teriflunomide in reducing the frequency of confirmed relapses
    Extension part:
    To assess long-term safety, tolerability and efficacy parameters in participants treated with remibrutinib
    Parte principal:
    Demostrar que remibrutinib es superior a teriflunomida para reducir la frecuencia de brotes confirmados.
    Parte de extensión:
    Evaluar los parámetros de seguridad, tolerabilidad y eficacia a largo plazo en participantes tratados con remibrutinib.
    E.2.2Secondary objectives of the trial
    Core
    Assess whether remibrutinib is superior to teriflunomide in
    - Delaying disability progression based on the pooled data from both identical pivotal studies
    - Reducing new inflammatory activity on MRI, based on MRI cohort data
    - Reducing neuronal damage
    - Disease-Activity-free status based on pooled data from both identical pivotal studies (MRI Cohort)
    Extension (exploratory)
    - Explore effect of remibrutinib versus terifunomide on brain MRI, relationship between remibrutinib exposure (PK) and efficacy and safety endpoints and relationship between potential biomarkers and their relationship with disease activity, disease course and treatment response
    - Perform exploratory pharmacogenetic analysis based on blood samples for DNA (optional)
    - Explore the effect of remibrutinib versus teriflunomide on disease activity free status and effect of remibrutinib versus teriflunomide on disability progression independent of relapse activity
    See protocol for complete list of objectives
    Principal
    Evaluar si remibrutinib es superior a teriflunomida en:
    - Retrasar la progresión de la discapacidad basándose en los datos agrupados de ambos estudios de registro idénticos
    - Reducir la nueva actividad inflamatoria en resonancia magnética (RM), basándose en los datos de la cohorte de RM
    - Reducir el daño neuronal
    - Estado libre de actividad de la enfermedad basándose en datos agrupados de ambos estudios de registro idénticos (cohorte de RM)
    Extensión (exploratoria)
    - Explorar el efecto de remibrutinib frente a teriflunomida en la RM cerebral, relación entre la exposición a remibrutinib (PK) y variables de eficacia y seguridad y relación entre los potenciales biomarcadores y su relación con la actividad de la enfermedad, curso de la enfermedad y respuesta a tratamiento
    - Realizar análisis farmacogenético exploratorio en muestras de sangre para ADN (opcional)
    Ver protocolo para la lista completa de objetivos
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1) DNA sampling / Pharmacogenetics
    The study includes an optional genetic research component. The purpose of genetic research may be to better understand the safety and efficacy of remibrutinib, or to learn more about human diseases, or to help develop ways to detect, monitor and treat diseases. As technology changes over time, the most appropriate technology will be used at the time the exploratory genetic research is performed. This may include the study of the entire genome. The use of DNA to search for biomarkers of disease and drug action is exploratory.

    2) MRI Cohort
    Only selected sites will participate in the MRI cohort; it is planned that approximately 400 participants will be included in this MRI cohort after signature of an additional (optional) consent. All eligible participants from these selected sites will undergo MRI scanning of the brain (see protocol for details)
    MRI scans will be transmitted by the sites to the central MRI reading center, designated by Novartis, for quality checks and central read. Further details on the image acquisition can be found in the MRI manual of the central MRI reading center. Details regarding the central read can be found in the central MRI reading center independent review charter.
    Each MRI scan performed for the study needs to be previewed by a local neuroradiologist/radiologist. The Investigator must be contacted in case of unexpected findings (e.g. not consistent with MS) detected on the MRI scan for safety actions and AE reporting.
    The MRIs required for the MRI cohort as part of this study are defined in the protocol. Routine MRIs that are mandated by the local treatment guidelines or local Health Authority will be conducted outside the trial (not sent to the central MRI reading center or included in the study database) for any participant.

    3) Additional Biomarker assessment
    Transcriptomic profiling may be assessed, using RNA from whole blood. mRNA expression patterns and patterns of other RNA species, will be derived from application of various technologies which may include sequencing of cDNA libraries related to the RNA extracted from blood. These analyses will be used to examine the effect of remibrutinib on transient RNA and may support the identification of pathways/markers that characterize the disease or response of treatment with remibrutinib. Due to exploratory nature, the data will not be recorded in the clinical database. For this Transcriptomics (RNA) assessment, PAXgene whole blood samples (one aliquot with 2.5 ml blood) will be collected at designated visits and stored for long-term storage. Transcriptomic assessment will be triggered based on results obtained in this study or other MS studies.

    4) PK sub-study - There will be two pharmacokinetic assessments (PK) cohorts, for "rich" and "sparse" sampling. “Rich PK sampling” will be performed in a minimum of 160 randomized participants (to ensure these are available for 80 completers per treatment arm), and requires sampling at Day 28 (M1) at pre-dose (0 h) and post-dose at the following times after dosing: 0.5 hour (± 15 mins), 1.0 hour (±15 mins), 2.0 hours (±15 mins), 3.0 hours (±30 mins) and 4.0 hours (±30 mins), and at M6 at pre-dose (0 h) and at 1.0 hour (±15 mins) post-dose. "Sparse PK sampling" will be performed in all other randomized participants and requires sampling at Day 28 (M1) and M6 at both pre-dose (0 h) and 1.0 hour (±15 mins) post-dose at both visits. PK assessments are only performed during the Core Part of the study
    1)Muestras de ADN/Farmacogenética
    El estudio incluye un componente de investigación genética opcional.El propósito de la investigación genética puede ser comprender mejor la seguridad y eficacia del remibrutinib,o aprender más sobre enfermedades humanas,o ayudar a desarrollar formas de detectar,monitorizar y tratar enfermedades.Como la tecnología puede cambiar con el tiempo,se utilizará la tecnología más adecuada en el momento en que se realice la investigación genética exploratoria.Esto puede incluir el estudio de todo el genoma.El uso del ADN para buscar biomarcadores de enfermedad y acción de fármacos es exploratorio.
    2)Cohorte de RM
    Solo los centros seleccionados participarán en la cohorte de RM;está previsto que se incluyan aproximadamente 400 participantes en esta cohorte de RM después de la firma de un consentimiento adicional (opcional).Todos los participantes elegibles de los centros seleccionados se someterán a una RM del cerebro (ver protocolo para detalles).
    Los centros enviarán las imágenes de RM al centro de lectura centralizada de RM,designado por Novartis,para los controles de calidad y la lectura centralizada. Se pueden encontrar más detalles sobre la adquisición de imágenes en el manual de RM del centro de lectura de RM central.Los detalles sobre la lectura central se pueden encontrar en la carta de revisión independiente del centro de lectura de RM central.
    Cada RM realizada en el estudio debe ser vista previamente por un neurorradiólogo/radiólogo local.El investigador debe ser contactado en caso de hallazgos inesperados (p.Ej.,No consistentes con EM)detectados en la RM para acciones de seguridad e informes de EA.
    Las RM requeridas para la cohorte de RM como parte de este estudio se definen en el prot.Las RM de rutina exigidas según las pautas de tratamiento (tto) locales o la autoridad sanitaria local se realizarán fuera del ensayo(no se enviarán al centro de lectura centralizada de RM ni se incluirán en la base de datos del estudio) para ningún participante.
    3)Evaluación adicional de Biomarcadores
    Se podría evaluar el perfil transcriptómico utilizando ARN de la sangre.Los patrones de expresión de ARNm y los patrones de otras especies de ARN se derivarán de la aplicación de diversas tecnologías que pueden incluir la secuenciación de bibliotecas de ADNc relacionadas con el ARN extraído de la sangre.Estos análisis se utilizarán para examinar el efecto de remibrutinib sobre el ARN transitorio y pueden respaldar la identificación de vías/marcadores que caracterizan la enfermedad o la respuesta al tto con remibrutinib.Debido a la naturaleza exploratoria,los datos no se registrarán en la base de datos clínica.Para esta evaluación de transcriptómica(ARN),se recolectarán muestras de sangre completa de PAXgene(una alícuota con 2,5 ml de sangre)en las visitas designadas y se guardarán para su almacenamiento a largo plazo.La evaluación transcriptómica se activará en función de los resultados obtenidos en este estudio u otros estudios de EM.
    4) Sub-estudio PK-Hay 2 cohortes PK para la «recogida de abundantes muestras y de escasas muestras».La «recogida de abundantes muestras para PK» se llevará a cabo en un mínimo de 160 participantes aleatorizados después de la firma de un consentimiento (opcional)adicional (para garantizar muestras de 80 participantes que hayan completado el tto por grupo de tto) y deben recogerse muestras el día 28 (M1) antes de la dosis (0 h) y en los siguientes momentos después de administrar la dosis:0,5 horas (±15 min),1 hora (±15 min),2 horas (±15 min),3 horas (±30 min) y 4 horas (±30 min) y en el M6 antes de la dosis (0 h) y 1 hora (±15 min) después de la dosis.La «recogida de escasas muestras para PK» se llevará a cabo en todos los demás participantes aleatorizados y deben recogerse muestras el día 28 (M1) y el M6 tanto antes de la dosis (0 h) como 1 hora (±15 min) después de la dosis en ambas visitas.Las muestras de PK son sólo recogidas durante la parte principal del estudio.
    E.3Principal inclusion criteria
    1. Signed informed consent obtained prior to any assessment performed (confirm at screening visit)
    2. Male or female participants 18 to 55 years of age (inclusive) at screening
    3. Diagnosis of RMS according to the 2017 McDonald diagnostic criteria (this would include relapsing-remitting course (RRMS) or secondary progressive (SPMS) course with disease activity) as confirmed at screening visit.
    4. At least: 1 documented relapse within the previous year, OR 2 documented relapses within the previous 2 years, prior to screening, OR 1 active Gadolinium (Gd)-enhancing lesion in the 12 months prior to screening
    5. EDSS score of 0 to 5.5 (inclusive) at screening and randomization
    6. Neurologically stable within 1 month prior to screening and randomization (including no MS relapse in this period)

    Please see protocol for complete detailed list of inclusion criteria
    1. Consentimiento informado firmado obtenido antes de realizar cualquier
    evaluación (debe confirmarse en la visita de selección).
    2. Participantes de ambos sexos con edades comprendidas entre los 18 y los 55 años (ambos incluidos) en la selección.
    3. Diagnóstico de EMR según los criterios diagnósticos de McDonald de
    2017 (esto incluiría esclerosis múltiple remitente recurrente (EMRR) o esclerosis
    múltiple secundaria progresiva (EMSP) con actividad de la enfermedad) confirmado
    en la visita de selección.
    4. Al menos: un brote documentado durante el año anterior
    O dos brotes documentados durante los dos años anteriores a la selección O una
    lesión activa captante de Gd en RM en los 12 meses anteriores a la selección.
    5.Puntuación de EDSS de 0 a 5,5 (inclusive) en la selección y la aleatorización.
    6. Estar neurológicamente estable durante el mes anterior a la selección y la
    aleatorización (sin presentar brote de esclerosis múltiple (EM) en este periodo).
    Por favor ver protocolo para una lista completa detallada de criterios de inclusión
    E.4Principal exclusion criteria
    1. Diagnosis of primary progressive multiple sclerosis (PPMS) according to the 2017 revision of the McDonald diagnostic criteria (Thompson et al 2018) at screening
    2. Disease duration of more than 10 years in participants with EDSS score of 2 or less at screening
    3. History of clinically significant CNS disease (e.g. stroke, traumatic brain or spinal injury, history or presence of myelopathy) or neurological disorders which may mimic MS at screening
    4. Ongoing substance abuse (drug or alcohol) or any other factor (e.g. serious psychiatric condition) that may interfere with the participant’s ability to cooperate and comply with the study procedures prior to randomization
    5. History of malignancy of any organ system (other than complete resection of localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases, at screening
    6. Participants with history of confirmed Progressive Multifocal Leukoencephalopathy (PML) or Neurological symptoms consistent with PML prior to randomization
    7. Women of child bearing potential unless they are using highly effective methods of contraception while taking study treatment and for at least 4 weeks after stopping study medication
    8. Sexually active males, unless they agree to use a condom while taking study treatment and for at least 4 weeks after stopping double blind study medication

    Please see protocol for complete detailed list of exclusion criteria
    1. Diagnóstico de esclerosis múltiple primaria progresiva (EMPP) según la revisión de 2017 de los criterios de diagnóstico de McDonald (Thompson et al 2018) en la selección.
    2. Duración de la enfermedad superior a 10 años en participantes con una puntuación de EDSS igual o inferior a 2 en la selección.
    3. Antecedentes de enfermedad del sistema nervioso central (SNC) clínicamente significativa (p. ej., ictus, lesión traumática cerebral o espinal, antecedentes o presencia de mielopatía) o trastornos neurológicos que puedan asemejarse a la EM en la selección.
    4. Abuso continuo de sustancias (drogas o alcohol) o cualquier otro factor (por ejemplo, una condición psiquiátrica grave) que pueda interferir con la capacidad del participante para cooperar y cumplir con los procedimientos del estudio antes de la aleatorización.
    5. Antecedentes de malignidad de cualquier sistema de órganos (que no sea la resección completa de un carcinoma de células basales localizado de la piel o cáncer de cuello uterino in situ), tratado o sin tratar, en los últimos 5 años, independientemente de si hay evidencia de recurrencia local o metástasis, en la selección.
    6. Participantes con antecedentes de leucoencefalopatía multifocal progresiva (LMP) confirmada o síntomas neurológicos acordes con la LMP antes de la aleatorización.
    7. Mujeres en edad fértil, a menos que estén usando métodos anticonceptivos altamente efectivos mientras reciben el tratamiento del estudio y durante al menos 4 semanas después de suspender la medicación del estudio.
    8. Hombres sexualmente activos, a menos que acepten usar un condón mientras reciben el tratamiento del estudio y durante al menos 4 semanas después de suspender la medicación del estudio doble ciego.
    Por favor ver protocolo para una lista completa detallada de criterios de exclusión
    E.5 End points
    E.5.1Primary end point(s)
    Core part:
    Annualized relapse rate (ARR) of confirmed relapses
    Extension Part:
    - Adverse events, laboratory data, vital signs, electrocardiogram (ECG),
    Columbia Suicide Severity Rating
    - ARR, number of new or enlarging T2 lesions on MRI per year
    (annualized T2 lesion rate), time to 6mCDP (EDSS), change in SDMT,
    NfL, Patient Reported Outcomes scores
    Parte principal:
    Tasa anualizada de brotes (TAB) de brotes confirmados.
    Parte de extensión:
    - Acontecimientos adversos, pruebas analíticas, constantes vitales, electrocardiograma (ECG), Columbia Suicide Severity Rating Scale
    - TAB, número de lesiones en T2 nuevas o aumentadas en RM (tasa anualizada de
    lesión T2), tiempo hasta PCD6m (EDSS), cambio en SDMT, NfL, Puntuación de los resultados reportados por pacientes
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 30 months
    Hasta 30 meses
    E.5.2Secondary end point(s)
    Core part:
    - Time to 3-month confirmed disability progression (3mCDP) on Expanded Disability Status Scale (EDSS)
    - Time to 6-month confirmed disability progression (6mCDP) on EDSS
    - Number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate)
    - Total number of Gd-enhancing T1 lesions per MRI scan
    - Neurofilament light chain (NfL) concentration in serum
    - Percentage of participants with No Evidence of Disease Activity-3 (NEDA-3), as assessed by absence of confirmed MS relapses, 6mCDP and new/enlarging T2 lesions on MRI

    Extension part (exploratory)
    - Annualized rate of brain volume loss (BVL), based on percentage brain volume change from baseline
    - Change from baseline in cortical grey matter volume, hemispheric white matter volume and thalamus volume
    - Slowly Expanding Lesions (SEL) in MRI
    - T2 lesions, ARR, 3mCDP, safety endpoints etc. (as applicable)
    - NfL, GFAP, total IgG, total IgM, B-cells, T2 lesions, ARR, 3mCDP etc. (as applicable)
    - Evaluate the relationship of genetic polymorphisms data with drug metabolism, the indication, the drug target pathway, and treatment response
    - Percentage of participants with NEDA-4, as assessed by the absence of confirmed MS relapses, 6mCDP, new/enlarging T2 lesions on MRI and brain volume loss > -0.4%/year
    - Time to 3mCDP, 6mCDP
    Parte principal:
    - Tiempo hasta la progresión confirmada de la discapacidad a los 3 meses (PCD3m) en la Expanded Disability Status Scale (EDSS)
    - Tiempo hasta la progresión confirmada de la discapacidad a los 6 meses (PCD6m) en EDSS.
    - Número de lesiones en T2 nuevas o aumentadas en RM por año (tasa anualizada de lesión T2)
    - Número de lesiones captantes de Gd en T1 con RM
    - Concentración de cadena ligera de los neurofilamentos (NfL) en suero
    - Porcentaje de pacientes con ninguna evidencia de actividad de la enfermedad (NEDA)-3, evaluada por la ausencia de brotes confirmados, PCD6m y lesiones nuevas/aumentadas en T2 en RM.

    Parte de extensión (exploratoria)
    - Tasa anualizada de pérdida de volumen cerebral (BVL), basada en el porcentaje de cambio de volumen cerebral desde la basal
    - Cambio desde la basal en el volumen de materia gris cortical, el volumen de materia blanca hemisférica y el volumen del tálamo.
    - Lesiones de expansión lenta (SEL) en MRI
    - Lesiones T2, TAB, PCD3m, evaluaciones de seguridad, etc. (según aplique)
    - NfL, GFAP, IgG total, IgM total, células B, lesiones T2, TAB, PCD3m, etc. (según aplique)
    - Evaluar la relación de los datos de polimorfismos genéticos con el metabolismo del fármaco, la indicación, la vía diana del fármaco y la respuesta al tratamiento.
    - Porcentaje de participantes con NEDA-4, evaluadas por la ausencia de brotes de EM, 6mCDP, lesiones nuevas/aumentadas en T2 en RM y pérdida de volumen cerebral > -0.4%/año
    - Tiempo hasta PCD3m, PCD6m
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up to 30 months.
    Hasta 30 meses
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    Tolerabilidad
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Doble enmascaramiento
    Double-dummy
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA75
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Brazil
    Canada
    China
    India
    Mexico
    Russian Federation
    South Africa
    Turkey
    United States
    Bulgaria
    Croatia
    Czechia
    Estonia
    France
    Germany
    Greece
    Hungary
    Italy
    Poland
    Portugal
    Romania
    Slovakia
    Slovenia
    Spain
    Sweden
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LSLV
    última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days24
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days9
    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: 800
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 373
    F.4.2.2In the whole clinical trial 800
    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)
    Participants who complete the core part of the study on study drug, can continue in the planned extension part. The investigator must provide follow-up medical care for all participants who do not enter the extension part or are prematurely withdrawn from the study, or must refer them for appropriate ongoing care.

    Please see protocol for more details.
    Los participantes que completen la parte principal del estudio del fármaco en estudio, pueden continuar en la parte de extensión planificada. El investigador debe brindar atención médica de seguimiento a todos los participantes que no entren en la parte de extensión o que se retiren prematuramente del estudio, o deben derivarlos para que reciban la atención continua adecuada.
    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 Decision2022-02-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-02-08
    P. End of Trial
    P.End of Trial StatusOngoing
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