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    Summary
    EudraCT Number:2014-002320-27
    Sponsor's Protocol Code Number:RPC01-301
    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:2015-02-09
    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 number2014-002320-27
    A.3Full title of the trial
    A Phase 3, multi-center, randomized, Double-Blind, double-dummy, active controlled, parallel group study to evaluate the efficacy and safety of RPC1063 administered orally to relapsing multiple sclerosis patients.
    Estudio de fase 3, multicéntrico, aleatorizado, doble ciego, con doble simulación, con control activo y de grupos paralelos para evaluar la eficacia y la seguridad de RPC1063 administrado por vía oral a pacientes con esclerosis múltiple recidivante
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to evaluate in a blinded and scientific way, the efficacy and safety of the new medicinal product RPC1063 in patients with Relapsing Multiple Sclerosis.
    Un estudio clínico para evaluar de modo ciego y científico, la eficacia y seguridad del nuevo producto medicinal RPC1063 en pacientes con recaida de Esclerosis Múltiple.
    A.3.2Name or abbreviated title of the trial where available
    Sunbeam
    A.4.1Sponsor's protocol code numberRPC01-301
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01628393
    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 SponsorReceptos, Inc.
    B.1.3.4CountryUnited States
    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 supportReceptos, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPPD
    B.5.2Functional name of contact pointPPD Project Manager
    B.5.3 Address:
    B.5.3.1Street AddressBornweg 12C
    B.5.3.2Town/ cityBennekom
    B.5.3.3Post code6721 AH
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+34900 834223
    B.5.6E-mailRegistroEspanolDeEstudiosClinicos@druginfo.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 name0.25mg RPC1063
    D.3.2Product code RPC1063
    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 INNOzanimod
    D.3.9.2Current sponsor codeRPC1063
    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: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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 name0.5mg RPC1063
    D.3.2Product code RPC1063
    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 INNOzanimod
    D.3.9.2Current sponsor codeRPC1063
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.50
    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 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 name1.0mg RPC1063
    D.3.2Product code RPC1063
    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 INNOzanimod
    D.3.9.2Current sponsor codeRPC1063
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.0
    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: 4
    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 Avonex
    D.2.1.1.2Name of the Marketing Authorisation holderBiogen Idec Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAvonex
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNInterferon beta-1a
    D.3.9.1CAS number 220581-49-7
    D.3.9.3Other descriptive nameINTERFERON BETA-1A
    D.3.9.4EV Substance CodeSUB12440MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboIntramuscular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsing Multiple Sclerosis
    Esclerosis Múltiple Recidivante
    E.1.1.1Medical condition in easily understood language
    Relapsing Multiple Sclerosis
    Esclerosis Múltiple Recidivante
    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 18.0
    E.1.2Level PT
    E.1.2Classification code 10048393
    E.1.2Term Multiple sclerosis relapse
    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 assess whether the clinical efficacy of RPC1063 is superior to interferon (IFN) ?-1a (Avonex®) in reducing the rate of clinical relapses in patients with RMS.
    Determinar si la eficacia clínica de RPC1063 es superior a la de interferón (IFN) ß 1a (Avonex®) en la reducción de la tasa de recidivas clínicas en pacientes con EMR.
    E.2.2Secondary objectives of the trial
    ? To assess the effect of RPC1063 on the proportion of patients with new/enlarging T2 lesions at Month 12
    ? To evaluate whether the efficacy of RPC1063 is superior to IFN ?-1a in delaying the accumulation of disability, as assessed by the Multiple Sclerosis Functional Composite (MSFC) and visual function as measured by the low-contrast letter acuity test (LCLA)
    ? To evaluate whether the efficacy of RPC1063 is superior to IFN ?-1a in delaying The accumulation of disability, as assessed by the Expanded Disability Status Scale (EDSS)
    ? To assess the effect of RPC1063 on brain atrophy over 12 months
    ? To evaluate the effect of RPC1063 on patient-reported quality of life as assessed by the Multiple Sclerosis Quality of Life-54 (MSQOL-54)
    ? To assess the safety and tolerability of RPC1063 in patients with RMS
    ?Evaluar el efecto de RPC1063 en el porcentaje de pacientes con lesiones en T2 nuevas o que aumenten de tamaño en el mes 12
    ?Determinar si la eficacia de RPC1063 es superior a la de IFN ?-1a en el retraso de la acumulación de discapacidad, evaluada mediante la escala MSFC (Escala funcional compuesta para la esclerosis múltiple) y la función visual determinada mediante la prueba de agudeza visual con letras de bajo contraste (LCLA)
    ?Determinar si la eficacia de RPC1063 es superior a la de IFN ?-1a en el retraso de la acumulación de discapacidad, evaluada mediante la escala EDSS (Escala ampliada del estado de discapacidad)
    ?Evaluar el efecto de RPC1063 en la atrofia cerebral durante 12 meses
    ?Evaluar el efecto de RPC1063 en la calidad de vida comunicada por el paciente, evaluada mediante la escala MSQOL 54 (Escala de calidad de vida en la esclerosis múltiple 54)
    ?Evaluar la seguridad y la tolerabilidad de RPC1063 en pacientes con EMR
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. MS, as diagnosed by the revised 2010 McDonald criteria
    2. Exhibiting a relapsing clinical course consistent with RMS and history of brain MRI lesions consistent with MS
    3. Ages 18-55 years, inclusive
    4. EDSS score between 0 and 5.0 at baseline
    5. Meet one of the following disease activity criteria:
    o At least 1 documented relapse within the last 12 months prior to screening
    OR
    o At least 1 documented relapse occurred within the last 24 months prior to screening and documented evidence of at least 1 GdE lesion on brain MRI within the last 12 months prior to randomization
    6. No history of relapse with onset from 30 days prior to screening until randomization; during this period, patients must have been clinically stable, without systemic corticosteroid treatment or adrenocorticotrophic hormone (ACTH)
    7. Ability to provide written informed consent and to be compliant with the schedule of protocol assessments
    8. Patients of reproduction potential (males and females) must practice an acceptable method of birth control (acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive, vasectomy, or double-barrier method [condom or diaphragm with spermicide]) during study participation and for 30 days after their last dose of treatment of study medication or true sexual abstinence (periodic abstinence [calendar, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
    9. Patients must have documentation of positive Varicella zoster virus (VZV) IgG antibody status or complete VZV vaccination at least 30 days prior to randomization
    1.EM, diagnosticada mediante los criterios modificados de McDonald de 2010.
    2.Presencia de una evolución clínica recidivante compatible con EMR y antecedentes de lesiones en la RM cerebral indicativas de EM.
    3.Edad de 18 55 años, ambos inclusive.
    4.Puntuación de la EDSS de 0 a 5,0 en el momento basal.
    5.Cumplimiento de uno de los siguientes criterios de actividad de la enfermedad:
    o Al menos una recidiva documentada en los 12 últimos meses previos a la selección
    O
    oAl menos una recidiva documentada en los 24 meses previos a la selección y signos documentados de al menos una lesión con CGd en la RM cerebral en los 12 meses previos a la aleatorización
    6.Ausencia de antecedentes de recidivas con comienzo entre 30 días antes de la selección y la aleatorización; durante este período, los pacientes deberán haber permanecido clínicamente estables, sin tratamiento con corticosteroides sistémicos ni corticotropina (ACTH).
    7.Capacidad de otorgar el consentimiento informado por escrito y de cumplir el calendario de evaluaciones del protocolo.
    8.Los pacientes con capacidad de procrear (varones y mujeres) deberán utilizar un método anticonceptivo aceptable (los métodos anticonceptivos aceptables en este estudio son: esterilización quirúrgica, dispositivos intrauterinos, anticonceptivo oral, parche anticonceptivo, anticonceptivo inyectable de acción prolongada, vasectomía o método de doble barrera [preservativo o diafragma con espermicida]) durante la participación en el estudio y durante 30 días después de su última dosis de medicación del estudio o verdadera abstinencia sexual (la abstinencia periódica [métodos del calendario, sintotérmico y postovulación] y la retirada no son métodos anticonceptivos aceptables)
    9.Los pacientes deben tener documentación de la presencia de anticuerpos IgG contra el virus de la varicela zóster (VVZ) o de una vacunación completa contra el VVZ al menos 30 días antes de la aleatorización
    E.4Principal exclusion criteria
    criterios de exclusión1. Primary progressive MS at screening
    2. Disease duration of more than 15 years in patients with an EDSS ?2.0
    3. Contraindications to MRI or Gadolinium contrast, such as known allergy to Gadolinium contrast dyes, renal insufficiency, claustrophobia, body size incompatible with the scanner, pacemaker, cochlear implants, intracranial vascular clips
    4. Incompatibility with beta IFN use (e.g. intolerable side effects)
    5. Pregnancy, lactation, or a positive serum beta human chorionic gonadotropin (?-hCG) measured during screening
    6. Clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, renal, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult or that would put the patient at risk by participating in the study in the opinion of treating investigator
    7. Specific cardiac conditions are excluded, including history or presence of:
    i. Recent (within the last 6 months) occurrence of myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, Class III/IV heart failure, sick sinus syndrome, or severe untreated sleep apnea
    ii. Prolonged QTcF interval (QTcF >450 msec males, >470 msec females), or at additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital long-QT syndrome, concurrent therapy with QT-prolonging drugs)
    iii. Patients with other pre-existing stable cardiac conditions who have not been cleared for the study by an appropriate cardiac evaluation by a cardiologist
    iv. Other clinically significant conduction abnormalities or any other significant cardiac condition that could jeopardize a patient?s health or put them at significant safety risk during the course of the study in the opinion of treating investigator
    8. Resting heart rate less than 55 bpm at Screening
    9. Diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with hemoglobin A1c >9% , or diabetic patients with significant co-morbid conditions such as retinopathy or nephropathy
    10. History of uveitis
    11. Known active bacterial, viral, fungal, mycobacterial infection, or other infection (including tuberculosis [TB] or atypical mycobacterial disease [but excluding fungal infection of nail beds, minor upper respiratory tract infections [URTI] and minor skin infections]) or any major episode of infection that required hospitalization or treatment with IV antibiotics within 30 days of screening or oral antibiotics within 14 days prior to screening
    12. History or known presence of recurrent or chronic infection; recurring urinary tract infections could be allowed
    13. History of cancer, including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have been excised and resolved)
    14. Suicide attempts in the past or current signs of major depression
    15. History of alcohol or drug abuse within 1 year prior to randomization
    16. History of or currently active primary or secondary immunodeficiency
    17. Prior use of any investigational agent within 6 months prior to enrollment
    18. Receipt of a live vaccine within 4 weeks prior to screening
    19. Non-lymphocyte-depleting disease-modifying MS agents must be discontinued from signing of informed consent
    20. Previous treatment with lymphocyte-depleting therapies
    21. Treatment with other immunosuppressant agents such as azathioprine, cyclosporine, methotrexate, or mycophenolate within 6 months prior to randomization
    22. Systemic corticosteroid therapy or ACTH use within 30 days prior to screening
    23. Prior treatment with lymphocyte trafficking blockers
    24. Treatment with intravenous immune globulin (IVIg) or plasmapheresis within 3 months prior to randomization
    25. Treatment with other disease modifying therapies within 3 months prior to randomization
    26. Intolerance of or contraindication to oral or IV corticosteroids
    27. Use of therapies that are not allowed based on CYP3A4 metabolism within 4 weeks prior to randomization
    28. Treatment with medications with a known impact on the cardiac conduction system are excluded
    29. Positive rapid plasma reagin
    30. Serum creatinine >1.4 mg/dL for women or >1.6 mg/dL for men
    31. Liver function impairment or persisting elevations of aspartate aminotransferase (SGOT/AST) or alanine aminotransferase (SGPT/ALT) >1.5 times the upper limit of normal (ULN), or direct bilirubin >1.5 times the ULN
    32. Hemoglobin <8.5 g/dL
    33. Clinically significant findings on brain MRI scan consistent with conditions other than MS
    34. ECG showing any clinically significant abnormality (e.g., acute ischemia, significant heart conduction abnormality (e.g., left bundle branch block)
    35. FEV1 or FVC <70% of predicted values at screening)
    36.Presence of >20 gadolinium-enhancing lesions on baseline brain MRI scan
    Please refer to the protocol for the remaining Exclusion Criteria
    1.EM progresiva primaria en selección
    2.Duración de enfermedad > a 15 años en pacientes con una puntuación en la EDSS menor o igual 2,0
    3.Contraindicaciones de la RM o del contraste con gadolinio, como alergia conocida a los medios de contraste, insuficiencia renal, claustrofobia, tamaño corporal incompatible con el escáner, marcapasos, implantes cocleares y grapas vasculares intracraneales
    4.Incompatibilidad con el uso de IFN ?
    5.Embarazo, lactancia o ? hCG + en suero medida durante la selección
    6.Enfermedad hepática, neurológica, respiratoria, oftalmológica, endocrina, renal u otra enfermedad sistémica grave clínicamente relevante que dificulte la aplicación del protocolo o la interpretación de los resultados del estudio o que pueda poner en peligro al paciente por participar en el estudio, según la opinión del investigador encargado del tratamiento.
    7.Se excluyen trastornos cardiacos específicos, como antecedentes o presencia de:
    i.Episodio reciente (en los 6 últimos meses) de infarto de miocardio, angina inestable, ictus, accidente isquémico transitorio, insuficiencia cardiaca descompensada con necesidad de hospitalización, insuficiencia cardiaca de clase III/IV, síndrome de disfunción sinusal o apnea del sueño grave no tratada
    ii.Prolongación del intervalo QTcF (QTcF >450 ms en los varones, >470 ms en las mujeres) o riesgo adicional de prolongación del QT iii.Pacientes con otras cardiopatías preexistentes que no se hayan esclarecido para el estudio mediante una evaluación cardiaca adecuada por un cardiólogo.
    iv.Otras alteraciones clínicamente importantes de la conducción o cualquier otro trastorno cardiaco significativo que puedan poner en peligro la salud de los pacientes o supongan un riesgo importante para la seguridad durante el estudio en opinión del investigador encargado del TTo
    8.Frecuencia cardíaca en reposo inferior a 55 lpm en selección
    9.Diabetes mellitus T1, o diabetes mellitus T2 no controlada con hemoglobina A1c >9 %, o pacientes diabéticos con enfermedades concomitantes importantes, como retinopatía o nefropatía
    10.Previa uveítis
    11.Infección bacteriana, viral, fúngica, micobacteriana o de otro tipo [pero excluyendo las micosis de los lechos ungueales, las infecciones de las vías respiratorias superiores [IVRS] de carácter leve y las infecciones cutáneas leves]) activa conocida o cualquier episodio grave de infección con necesidad de hospitalización o TTo con antibióticos IV en 30 días previos a selección o con antibióticos orales en 14 días previos a selección
    12.Antecedentes o presencia conocida de una infección recurrente o crónica; podría permitirse la existencia de infecciones urinarias recurrentes
    13.Antecedentes de cáncer,tumores sólidos y neoplasias hematológicas malignas (excepto carcinomas basocelulares y espinocelulares in situ de piel que hayan sido extirpados y se hayan resuelto).
    14.Intentos de suicidio previos o depresión mayor presente
    15.Antecedentes de alcoholismo o toxicomanía en el año previo a la aleatorización
    16.Antecedentes o presencia activa de una inmunodeficiencia primaria o secundaria
    17.Uso anterior de cualquier fármaco en investigación en 6 meses previos a la inscripción
    18.Vacunación con microorganismos vivos en las 4 semanas previas a selección
    19.fármacos para EM que sean modificadores de enfermedad pero sin reducir los linfocitos deberán suspenderse desde la firma del CI
    20.TTo previo con modalidades que reduzcan los linfocitos
    21.TTo con otros inmunodepresores en los 6 meses previos a la aleatorización
    22.TTo con corticosteroides sistémicos o uso de ACTH en los 30 días previos a la selección
    23.TTo previo con bloqueantes del tráfico de linfocitos
    24.TTo con inmunoglobulina intravenosa o plasmaféresis en los 3 meses previos a la aleatorización
    25.TTo con otros medicamentos modificadores de la enfermedad en los 3 meses previos a la aleatorización
    26.Intolerancia a corticosteroides o contraindicación para recibirlos.
    27.Uso de TTos prohibidos en función del metabolismo por la CYP3A4 en 4 semanas previas a aleatorización.
    28.Se excluye el TTo con medicamentos con un efecto conocido en el sistema de conducción cardiaco
    29.Resultado positivo para reagina plasmática rápida
    30.Creatinina sérica > 1,4 mg/dl en mujeres o > 1,6 mg/dl en varones
    31.Insuficiencia hepática o elevaciones persistentes de la aspartato aminotransferasa (SGOT/AST) o la alanina aminotransferasa (SGPT/ALT) > 1,5 veces el límite superior de la normalidad (LSN) o bilirrubina directa > 1,5 veces el LSN
    32.Hemoglobina < 8,5 g/dl
    33.Hallazgos clínicamente significativos en la RM cerebral compatibles con enfermedades distintas de la EM
    34.ECG con anomalías clínicamente significativas ( o alteración significativa de la conducción cardíaca
    35.FEV1 o FVC <70 % de los valores teóricos en la selección
    36.Presencia de > 20 lesiones realzadas con gadolinio en la RM cerebral basal.
    Por favor refierase al protocolo por los restantes criterios de exclusión
    E.5 End points
    E.5.1Primary end point(s)
    ? Annual relapse rate (ARR) during the treatment period
    TRA durante el período de tratamiento
    E.5.1.1Timepoint(s) of evaluation of this end point
    Please see Section E.5.1 above
    Por favor ver sección E.5.1 arriba
    E.5.2Secondary end point(s)
    ? The number of new or enlarging hyperintense T2-weighted brain MRI lesions over 12 months
    ? The number of GdE brain MRI lesions at Month 12
    ? Time to onset of disability progression as defined by a sustained worsening in EDSS of 1.0 points or more, confirmed after 3 months and after 6 months
    ? Proportion of patients who are GdE lesion-free at Month 12
    ? Proportion of patients who are new or enlarging T2 lesion-free at Month12
    ? The percent change in normalized brain volume (atrophy) on brain MRI scans from Baseline to Month 12
    ? Change in MSFC score from Baseline to Month 12 (including the Low-Contrast Letter Acuity Test [LCLA] measurement of visual function as a component)
    ? Change in MSQOL-54 score from Baseline to Month 12
    ?Número de lesiones hiperintensas ponderadas en T2 nuevas o que aumenten de tamaño en la RM cerebral durante 12 meses
    ?Número de lesiones con CGd en la RM cerebral a los 12 meses
    ?Tiempo hasta la aparición de progresión de la discapacidad, definida como un empeoramiento mantenido de la puntuación de la EDSS de 1,0 puntos o más, confirmado después de 3 meses y después de 6 meses
    ?Porcentaje de pacientes sin lesiones con CGd a los 12 meses
    ?Porcentaje de pacientes sin lesiones en T2 nuevas o que aumenten de tamaño a los 12 meses
    ?Variación porcentual del volumen cerebral normalizado (atrofia) en las RM cerebrales entre el momento basal y el mes 12
    ?Variación de la puntuación de la MSFC entre el momento basal y el mes 12 (incluida la medición de la función visual como componente en la Prueba de agudeza con letras de bajo contraste [LCLA])
    ?Variación de la puntuación de la MSQOL 54 entre el momento basal y el mes 12
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please see Section E.5.2 above
    Por favor ver sección E.5.2 arriba
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic 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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    doble simulación
    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 trial3
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA86
    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
    Austria
    Belarus
    Bosnia and Herzegovina
    Brazil
    Bulgaria
    Canada
    Colombia
    Czech Republic
    Estonia
    Georgia
    Germany
    Latvia
    Mexico
    Moldova, Republic of
    Netherlands
    New Zealand
    Peru
    Poland
    Portugal
    Romania
    Russian Federation
    Serbia
    South Africa
    Spain
    Sweden
    Switzerland
    Ukraine
    United States
    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
    LVLS
    UVUP ( última visita ultimo paciente)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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 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: 1200
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 773
    F.4.2.2In the whole clinical trial 1200
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard of Care
    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 Decision2015-04-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-12-22
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