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    Summary
    EudraCT Number:2020-004128-41
    Sponsor's Protocol Code Number:WN42086
    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:2021-07-27
    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 number2020-004128-41
    A.3Full title of the trial
    A PHASE III MULTICENTER, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY STUDY TO EVALUATE SAFETY AND EFFICACY OF OCRELIZUMAB IN COMPARISON WITH FINGOLIMOD IN CHILDREN AND ADOLESCENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS
    ESTUDIO DE FASE III, MULTICÉNTRICO, ALEATORIZADO, DOBLE CIEGO Y CON DOBLE SIMULACIÓN PARA EVALUAR LA SEGURIDAD Y LA EFICACIA DE OCRELIZUMAB EN COMPARACIÓN CON FINGOLIMOD EN NIÑOS Y ADOLESCENTES CON ESCLEROSIS MÚLTIPLE ESCLEROSIS MÚLTIPLE REMITENTE-RECURRENTE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate Safety and Efficacy of Ocrelizumab in Comparison with Fingolimod in Children and Adolescents with Relapsing-Remitting Multiple Sclerosis
    Estudio para evaluar la seguridad y eficacia de ocrelizumab en comparación con fingolimod en niños y adolescentes con esclerosis múltiple remitente recurrente
    A.4.1Sponsor's protocol code numberWN42086
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/493/2020
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd.
    B.1.3.4CountrySwitzerland
    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 supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF. Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.5Fax number913248196
    B.5.6E-mailspain.start_up_unit@roche.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 Ocrevus
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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.3.4Pharmaceutical form Concentrate 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 INNOcrelizumab
    D.3.9.1CAS number 637334-45-3
    D.3.9.2Current sponsor codeRO4964913
    D.3.9.3Other descriptive nameOCRELIZUMAB
    D.3.9.4EV Substance CodeSUB121707
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 Yes
    D.3.11.13.1Other medicinal product typehumanized monoclonal antibody
    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
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.4Pharmaceutical 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 162359-55-9
    D.3.9.2Current sponsor codeRO7079904
    D.3.9.3Other descriptive nameFINGOLIMOD
    D.3.9.4EV Substance CodeSUB31908
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.25
    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: 3
    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
    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.3.4Pharmaceutical 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 162359-55-9
    D.3.9.2Current sponsor codeRO7079904
    D.3.9.3Other descriptive nameFINGOLIMOD
    D.3.9.4EV Substance CodeSUB31908
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    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
    Relapsing-Remitting Multiple Sclerosis
    Esclerosis múltiple remitente-recurrente
    E.1.1.1Medical condition in easily understood language
    Multiple sclerosis is a disabling disease of brain and spinal cord that disrupts flow of information within brain, characterized by flare-ups with periods of remission in between (relapsing remitting)
    La EM es una enf incapacitante del cerebro y la ME que interrumpe el flujo de información dentro del cerebro, caracterizada por brotes con períodos de remisión intermedios (remisión recurrente)
    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 21.1
    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
    • To demonstrate non-inferiority of ocrelizumab compared with fingolimod, based on Protocol-defined annualized relapse rate (ARR)
    • Demostrar la no inferioridad de ocrelizumab en comparación con fingolimod, según la tasa de recaída anualizada definida por el protocolo (ARR)
    E.2.2Secondary objectives of the trial
    • To demonstrate non-inferiority of ocrelizumab compared with fingolimod based on the number of new or enlarging T2-hyperintense lesions (T2 lesions) as detected by brain MRI
    • To demonstrate the superiority of ocrelizumab versus fingolimod based on the number of new or enlarging T2-hyperintense lesions, number of T1 gadolinium lesions and protocol-defined ARR
    • To evaluate the safety of ocrelizumab administered by intravenous (IV) infusion every 24-weeks compared with fingolimod administered once a day (QD) by mouth (PO)
    • To assess the pharmacokinetics of ocrelizumab in all children/adolescents enrolled in this study
    • To assess the pharmacodynamics in all children/adolescents enrolled in this study, as measured by blood B-cell count
    • To evaluate the immune response to ocrelizumab
    • Demostrar la no inferioridad de ocrelizumab en comparación con fingolimod en función del número de lesiones hiperintensas en T2 nuevas o agrandadas (lesiones T2) detectadas por resonancia magnética cerebral
    • Demostrar la superioridad de ocrelizumab frente a fingolimod en función del número de lesiones hiperintensas en T2 nuevas o agrandadas, el número de lesiones de gadolinio en T1 y la ARR definida por el protocolo
    • Evaluar la seguridad de ocrelizumab administrado por infusión intravenosa (IV) cada 24 semanas en comparación con fingolimod administrado una vez al día (QD) por vía oral (PO)
    • Evaluar la farmacocinética de ocrelizumab en todos los niños / adolescentes incluidos en este estudio.
    • Evaluar la farmacodinamia en todos los niños / adolescentes inscritos en este estudio, medida por el recuento de células B en sangre.
    • Evaluar la respuesta inmune al ocrelizumab.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    General Inclusion Criteria
    • Able to comply with the study protocol, in the investigator's judgment
    • Age between >10 to <18 years at randomization
    • Body weight >=25 kilograms
    • Children and adolescents must have received all childhood vaccinations as per local and/or national recommendations for childhood vaccination against infectious diseases
    • Female patients of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for at least 24 weeks after the final dose of ocrelizumab/ocrelizumab placebo and for 2 months after the final dose of fingolimod/fingolimod placebo
    Inclusion Criteria Related to Pediatric Multiple Sclerosis
    • Diagnosis of relapsing-remitting multiple sclerosis (RRMS) in accordance with the international pediatric multiple sclerosis study group (IPMSSG) criteria for pediatric MS, Version 2012, or McDonald criteria 2017 (or the most current revision of the IPMSSG criteria or McDonald criteria at the time of study start)
    • Confirmation of the diagnosis of Pediatric RRMS by the Independent Review of Eligibility Committee prior to randomization
    • Expanded disability status scale (EDSS) at screening: 0-5.5, both inclusive
    • Neurologic stability for >=30 days prior to screening, and between screening and Day 1
    • At least one relapse during the year prior to screening or two relapses in the previous two years prior to screening or evidence of at least one Gd enhancing lesion on MRI within 6 months prior to randomization (including screening MRI)
    Criterios generales de inclusión
    • Capaz de cumplir con el protocolo del estudio, a juicio del investigador
    • Edad entre> 10 y <18 años en el momento de la aleatorización
    • Peso corporal> = 25 kilogramos
    • Los niños y adolescentes deben haber recibido todas las vacunas infantiles según las recomendaciones locales y / o nacionales para la vacunación infantil contra enfermedades infecciosas.
    • Las pacientes en edad fértil deben aceptar permanecer en la abstinencia (abstenerse de las relaciones heterosexuales) o utilizar métodos anticonceptivos durante el período de tratamiento y durante al menos 24 semanas después de la dosis final de ocrelizumab / ocrelizumab placebo y durante 2 meses después de la dosis final de fingolimod / placebo de fingolimod
    Criterios de inclusión relacionados con la esclerosis múltiple pediátrica
    • Diagnóstico de esclerosis múltiple remitente-recurrente (EMRR) de acuerdo con los criterios del grupo de estudio de esclerosis múltiple pediátrica internacional (IPMSSG) para EM pediátrica, versión 2012, o los criterios de McDonald 2017 (o la revisión más actual de los criterios de IPMSSG o de McDonald en la hora de inicio del estudio)
    • Confirmación del diagnóstico de EMRR pediátrica por parte del Comité de Revisión Independiente de Elegibilidad antes de la aleatorización
    • Escala ampliada del estado de discapacidad (EDSS) en el momento de la selección: 0-5,5, ambos incluidos
    • Estabilidad neurológica durante> = 30 días antes del cribado y entre el cribado y el día 1
    • Al menos una recaída durante el año anterior al cribado o dos recaídas en los dos años anteriores al cribado o evidencia de al menos una lesión que realza Gd en la resonancia magnética dentro de los 6 meses previos a la aleatorización (incluida la resonancia magnética de cribado)
    E.4Principal exclusion criteria
    Exclusions Related to General Health
    • Pregnancy or lactation
    • Known presence or suspicion of other neurologic disorders that may mimic MS
    • Aquaporin-4 positive and/or myelin oligodendrocyte glycoprotein antibody positive at screening
    • Clinical or laboratory findings at first presentation not typically for MS
    • Abnormal findings in the cerebrospinal fluid at first presentation
    • Atypical magnetic resonance imaging (MRI) findings
    • Significant uncontrolled somatic diseases or any other significant condition
    • Known active bacterial, viral, fungal, mycobacterial infection, or other infection
    • Infection requiring hospitalization or treatment with IV anti-infective agents within 4 weeks prior to Day 1 visit or oral anti-infective agents within 2 weeks prior to Day 1 visit
    • History or known presence of recurrent or chronic infection
    • Receipt of a live or live-attenuated vaccine within 6 weeks prior to treatment allocation
    • History or laboratory evidence of clinically significant coagulation disorders
    • Peripheral venous access that precludes IV administration and venous blood sampling
    • Inability to complete MRI scan
    • Teeth braces interfering with MRI acquisition
    • History of cancer
    • Currently active or history of alcohol or drug abuse
    Exclusion Criteria Related to General Health Specific to Fingolimod Treatment
    • History of symptomatic bradycardia, recurrent syncope, significant QT prolongation. Patients having risk factors for QT prolongation such as hypokalemia or congenital QT prolongation, and uncontrolled hypertension
    • Patients who in the previous 6 months had myocardial infarction, unstable angina pectoris, stroke/transient ischemic attack, decompensated heart failure, or New York Heart Association Class III/IV heart failure
    • Patients with severe cardiac arrhythmias
    • Patients with second-degree Mobitz type II atrioventricular (AV) block or third-degree AV block, sick-sinus syndrome or sinoatrial heart block
    • Patients with a baseline QTc interval >=500 milliseconds
    • Presence of macular edema
    • Presence of any pulmonary conditions, as determined by the investigator
    • History of any type of epileptic seizure(s) as well as psychogenic non-epileptic seizure(s) during the past 12 months before screening
    • Patients with chronic liver or biliary disease, acute or chronic pancreatitis
    Exclusion Criteria Related to Medications
    • History of a severe allergic or anaphylactic reaction to humanized or murine MAbs or known hypersensitivity to any component of ocrelizumab solution
    • Contraindications to or intolerance of oral or IV corticosteroids, antihistamines, or antipyretics
    • Treatment with any investigational agent within 24 weeks of screening or 5 half-lives
    • Previous treatment with B-cell−targeted therapies
    • Any previous treatment with alemtuzumab, anti-CD4, cladribine, mitoxantrone, daclizumab, laquinimod, total body irradiation, or bone marrow transplantation
    • Treatment with cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, or methotrexate within 24 months prior to treatment allocation
    • Treatment with natalizumab within 12 months prior to randomization
    • Previous treatment with fingolimod
    • Treatment with teriflunomide or any other S1P receptor modulator within 24 weeks prior to treatment allocation
    • Treatment with dimethyl fumarate within 4 weeks prior to treatment allocation
    • Treatment with intravenous immunoglobulin within 12 weeks prior to treatment allocation
    • Treatment with plasmapheresis within 4 weeks prior to treatment allocation
    • Completion of systemic corticosteroid therapy within 30 days prior to screening
    Exclusion Criteria Related to Medications Specific to Fingolimod Treatment
    • History of a severe allergic reaction or known hypersensitivity to any component of fingolimod tablet
    • Treatment with beta-blockers or calcium-channel blockers
    • Patient treated with digoxin, anticholinesteratic agents, pilocarpine
    • Anti-arrhythmic drugs of Class Ia and III
    Exclusion Criteria Related to Laboratory Findings
    • Positive screening tests for serum beta-human chorionic growth hormone (beta-hCG) or hepatitis B or hepatitis B core antibody or hepatitis C antibody or rapid plasma reagin
    • Positive serological testing for myelin oligodendrocyte glycoprotein (MOG) antibody, human immunodeficiency virus (HIV), tuberculosis
    • Positive pregnancy test
    • Negative serological testing for varicella zoster
    • CD4: <30%, Serum IgG: 18% below the lower limit of normal (LLN), Serum IgM: 8% below the LLN, Neutrophil Count <1.5*10^3 per microliter, Lymphocyte: below the LLN
    • Patients with ALT, AST, Alkaline phosphatase, y-GGT> 2x Upper Limit of Normal range for age
    Exclusiones relacionadas con la salud general
    • Embarazo o lactancia
    • Presencia conocida o sospecha de otros trastornos neurológicos que pueden simular la EM.
    • Acuaporina-4 positivo y / o anticuerpo de glucoproteína oligodendrocitaria de mielina positivo en la selección
    • Hallazgos clínicos o de lab en la primera presentación no típicamente de la EM
    • Hallazgos anormales en el líquido cefalorraquídeo en la primera presentación
    • Hallazgos atípicos de la resonancia magnética (IRM)
    • Enf somáticas impt no controladas o cualquier otra afección significativa
    • Infec bacteriana, viral, micótica o micobacteriana activa conocida u otra infec
    • Infec que requiera hospitalización o tto con agentes antiinfecciosos intravenosos dentro de las 4 semanas anteriores a la visita del Día 1 o agentes antiinfecciosos orales dentro de las 2 semanas anteriores a la visita del Día 1
    • Historia o presencia conocida de infección crónica o recurrente
    • Recepción de una vacuna viva o atenuada en las 6 semanas anteriores a la asignación del tto
    • Historial o evidencia de lab de trastornos de la coagulación clínicamente significativos
    • Acceso venoso periférico que impide la adm intravenosa y la toma de muestras de sangre venosa
    • Incapacidad para completar RM
    • Aparatos ortopédicos q interfieran con la RM
    • Historia de cáncer
    • Activo o antecedentes de buso de alcohol o drogas
    Criterios de excl relacionados con la salud general específicos del tto con fingolimod
    • Historia de bradicardia sintomática, síncope recurrente, prolongación significativa QT. Pcts con factores de riesgo de prolongación del intervalo QT, como hipopotasemia o prolongación congénita del intervalo QT, e hiperT no controlada.
    • Pcts que en los 6 meses anteriores tuvieron infarto de miocardio, angina de pecho inestable, accidente cerebrovascular / ataque isquémico transitorio, insufiC cardíaca descompensada o insuficiencia cardíaca de clase III / IV de la New York Heart Association
    • Pcts con arritmias cardíacas graves
    • Pcts con bloqueo auriculoventricular (AV) de segundo grado Mobitz tipo II o bloqueo AV de tercer grado, síndrome del seno enfermo o bloqueo cardíaco sinoauricular
    • Pcts con un intervalo QTc basal> = 500 mseg
    • Presencia de edema macular
    • Presencia de condición pulmonar
    • Historial de convulsiones epilépticas, así como convulsiones psicógenas no epilépticas durante los últimos 12 meses antes de la evaluación
    • Pcts con enf hepática o biliar crónica, pancreatitis aguda o crónica
    Criterios de exc relac con medicamentos
    • Historial de reacción alérgica o anafiláctica grave a MAbs humanizados o murinos o hipersensibilidad conocida a componenteS de la solución de ocre
    • Contraindic o intolerancia a los corticosteroides, antiH1 o antipiréticos orales o IV
    • Tto con cualquier agente en investigación dentro de las 24 semanas posteriores a la detección o las 5 vidas medias
    • Tto previo con terapias dirigidas a células B
    • Cualquier tto previo con alemtuzumab, anti-CD4, cladribina, mitoxantrona, daclizumab, laquinimod, irradiación corporal total o trasplante de médula ósea
    • Tcon ciclofosto famida, azatioprina, micofenolato de mofetilo, ciclosporina o metotrexato en los 24 meses anteriores a la asignación del tto.
    • Tto con natalizumab en los 12 meses anteriores a la aleatorización
    • Tto previo con fingolimod
    • Tto con teriflunomida o cualquier otro modulador del receptor S1P EN las 24 semanas previas a la asignación del tro
    • Tto con dimetilfumarato en las 4 semanas anteriores a la asignación al tto
    • Tto con InmG intravenosa dentro de las 12 semanas previas a la asignación del tto.
    • Tto con plasmaféresis en las 4 semanas previas a la asignación al tto
    • Finalización de la terapia con corticosteroides sist dentro de los 30 días previos a la selección
    Criterios de exclusión relacionados con medicamentos específicos para el tto con fingolimod
    • Historial de reacción alérgica grave o hipersensibilidad conocida a cualquier componente del fingolimod
    • Tto con betabloqueantes o bloqueadores de los canales de calcio
    • Pct tratado con digoxina, agentes anticolinesteráticos, pilocarpina
    • Fármacos antiarrítmicos de clase Ia y III
    Criterios de exclusión relacionados con los hallazgos de laboratorio
    • Pruebas de detección positivas para la hormona beta-hCG en suero o el AntiC del núcleo de la hepatitis B o de la hepatitis B o el anticuerpo de la hepatitis C o la reagina plasmática rápida
    • Prueba serológica positiva para antiC de glucoproteína oligodendrocitaria de mielina (MOG), VIH, tuberculosis
    • Prueba de embarazo positiva
    • Pruebas serológicas negativas para varicela zoster
    • CD4: <30%, IgG en suero: 18% por debajo del límite inferior de lo normal (LIN), IgM en suero: 8% por debajo del LIN, Recuento de neutrófilos <1,5 * 10 ^ 3 por microlitro, Linfocitos: por debajo del LIN
    • Pcts con ALT, AST, fosfatasa alcalina, y-GGT> 2 veces el límite superior del rango normal para la edad
    E.5 End points
    E.5.1Primary end point(s)
    1. Protocol-defined annualized relapse rate (ARR) (non-inferiority)
    1. Tasa de recaída anualizada definida por el protocolo (ARR) (no inferioridad)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 2 years
    1. Hasta aproximadamente 2 años
    E.5.2Secondary end point(s)
    1. Number of new or enlarging T2 lesions as detected by brain MRI during the double-blind period
    2. Number of new or enlarging T2 lesions by Week 96 (non-inferiority)
    3. Protocol-defined ARR by Week 96 (non-inferiority)
    4. Number of T1 gadolinium (Gd) lesions at Week 12
    5. Protocol-defined ARR during the double-blind period (superiority)
    6. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)
    7. Change from baseline in targeted vital signs and clinical significant abnormalities in electrocardiogram (ECG) parameters
    8. Change from baseline in targeted clinical laboratory test results
    9. Concentrations of ocrelizumab at indicated time points
    10. Levels of CD19 B-cell count in blood
    11. Prevalence of anti-drug antibodies (ADAs) against ocrelizumab at baseline
    12. Incidence of ADAs against ocrelizumab during the study
    1. Número de lesiones T2 nuevas o agrandadas detectadas por resonancia magnética cerebral durante el período doble ciego
    2. Número de lesiones T2 nuevas o agrandadas en la semana 96 (no inferioridad)
    3. ARR definido por el protocolo en la semana 96 (no inferioridad)
    4. Número de lesiones de gadolinio (Gd) T1 en la semana 12
    5. ARR definido por el protocolo durante el período de doble ciego (superioridad)
    6. Incidencia y gravedad de los eventos adversos, con la gravedad determinada de acuerdo con los Criterios de terminología común para eventos adversos del National Cancer Institute, versión 5.0 (NCI CTCAE v5.0)
    7. Cambio desde el valor inicial en los signos vitales específicos y anomalías clínicamente significativas en los parámetros del electrocardiograma (ECG)
    8. Cambio con respecto al valor inicial en los resultados de las pruebas de laboratorio clínico específicas
    9. Concentraciones de ocrelizumab en los puntos temporales indicados
    10. Niveles de recuento de células B CD19 en sangre
    11. Prevalencia de anticuerpos antidrogas (ADA) contra ocrelizumab al inicio del estudio
    12. Incidencia de ADA contra ocrelizumab durante el estudio
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 2 years
    2-3. At Week 96
    4. At Week 12
    5. Up to approximately 2 years
    6. Up to 48 weeks from the date of last infusion of ocrelizumab
    7-8. Baseline to 48 weeks from the date of last infusion of ocrelizumab
    9. Weeks 1, 2, 12, 24, 36, 48, 60, 72, 84 and 96
    10. Baseline to 48 weeks from the date of last infusion of ocrelizumab
    11. At Baseline (Week -8 to -1)
    12. Weeks 1, 24, 48, 72, 96; OLE Period: Day 1 of Dose 1 and of all doses afterword’s; Safety Follow up: 12, 36, 60, 84, 108, 132 weeks from the date of last infusion of ocrelizumab
    1. Hasta aproximadamente 2 años
    2-3. En la semana 96
    4. En la semana 12
    5. Hasta aproximadamente 2 años
    6. Hasta 48 semanas desde la fecha de la última infusión de ocrelizumab
    7-8. Valor inicial hasta 48 semanas desde la fecha de la última perfusión de ocrelizumab
    9. Semanas 1, 2, 12, 24, 36, 48, 60, 72, 84 y 96
    10. Valor inicial hasta 48 semanas desde la fecha de la última infusión de ocrelizumab
    11. Al inicio del estudio (semana -8 a -1)
    12. Semanas 1, 24, 48, 72, 96; Período OLE: Día 1 de la dosis 1 y de todas las dosis posteriores; Seguimiento de seguridad: 12, 36, 60, 84, 108, 132 semanas a partir de la fecha de la última infusión de ocrelizumab
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    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 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA80
    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
    Brazil
    Canada
    Mexico
    Russian Federation
    Serbia
    Turkey
    Ukraine
    United States
    Austria
    Belgium
    Bulgaria
    Denmark
    France
    Germany
    Hungary
    Italy
    Netherlands
    Poland
    Portugal
    Romania
    Spain
    Switzerland
    United Kingdom
    Czechia
    Argentina
    Greece
    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
    The end of study is defined as either the last patient, last visit (LPLV) of the study or the LPLV in the SFU or B-cell monitoring period of the SFU, whichever is later, or when the Sponsor decides to discontinue the study or development program in pediatric MS.
    Al final del estudio se define como la última visita del ultimo paciente (LPLV) del estudio o el LPLV en la SFU o el período de monitorización de células B de la SFU, lo que ocurra más tarde, o cuando el Patrocinador decide interrumpir el estudio o programa de desarrollo en EM pediátrica.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 233
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 23
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 210
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Informed consent for study participation signed by the parents or a legal guardian, with patient assent obtained verbally and when possible, in writing, from all pediatric patients old enough to fully comprehend the assent document
    CI para la participación firmado por los padres o tutor legal, con el CI del pct obtenido verbalmente y, cuando sea posible, por escrito, de los pct pediátricos con la edad suf. para comprender el CI
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 115
    F.4.2.2In the whole clinical trial 233
    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)
    Currently, the Sponsor does not have any plans to provide ocrelizumab or any other study treatments to patients who have completed the study. The Sponsor may evaluate whether to continue providing ocrelizumab in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, available at the following website:
    http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
    Actualmente, el promotor no tiene planes de proporcionar ocrelizumab ni ningún otro tratamiento del estudio a los pacientes que completaron el estudio. El Patrocinador puede evaluar si continúa proporcionando ocrelizumab de acuerdo con la Política global de Roche sobre acceso continuo a medicamentos en investigación, disponible en el siguiente sitio web:
    http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Connect4Children (C4C)
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-02-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-21
    P. End of Trial
    P.End of Trial StatusOngoing
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