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    Summary
    EudraCT Number:2013-003126-83
    Sponsor's Protocol Code Number:EMR200559005
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-03-05
    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 number2013-003126-83
    A.3Full title of the trial
    A Phase III, Randomized, Double-Blind, Double Dummy, Multicenter Trial Comparing the Efficacy and Safety of 2 Doses of Daily Oral ONO 4641 (0.05 mg and 0.1 mg) versus Interferon-?-1a 30 µg IM Weekly in Subjects with Relapsing Multiple Sclerosis
    Ensayo multicéntrico de fase III, aleatorizado, doble ciego y con doble simulación para comparar la eficacia y la seguridad de 2 dosis orales diarias de ONO-4641 (0,05 mg y 0,1 mg) con la administración intramuscular semanal de 30 µg de interferón-beta-1a en sujetos con esclerosis múltiple recidivante
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study which compares the effectiveness and safety of a not yet approved drug called ONO-4641 versus an approved drug called interferon beta 1a (active comparator) in patients with multiple sclerosis. The study is double-blind (that is when neither the patient nor the investigator know which of the 2 drugs the patient is receiving). Patients will be randomly assigned (like the flip of a coin) to receive the study drug (two different doses) or the comparator.
    A.3.2Name or abbreviated title of the trial where available
    Efficacy and safety of ONO-4641 versus Interferon-?-1a in patients with multiple sclerosis
    Eficacia y seguridad de ONO-4641 frente a Interferón -?-1a en pacientes con esclerosis múltiple
    A.4.1Sponsor's protocol code numberEMR200559005
    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 SponsorMerck KGaA
    B.1.3.4CountryGermany
    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 supportMerck KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck KGaA
    B.5.2Functional name of contact pointCommunication Centre merck KGaA
    B.5.3 Address:
    B.5.3.1Street AddressFrankfurter Strasse 250
    B.5.3.2Town/ cityDarmstadt
    B.5.3.3Post code64293
    B.5.3.4CountryGermany
    B.5.4Telephone number496151725200
    B.5.6E-mailservice@merckgroup.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.3.2Product code MSC2430913A or ONO-4641 (to be used as synonyms)
    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 INNCeralifimod
    D.3.9.1CAS number 891859-12-4
    D.3.9.2Current sponsor codeMSC2430913A or ONO-4641 (to be used as synonyms)
    D.3.9.3Other descriptive nameONO-4641
    D.3.9.4EV Substance CodeSUB30962
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.05
    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 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 infusion in pre-filled syringe
    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 INNAvonex
    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/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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 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.3.2Product code MSC2430913A or ONO-4641 (to be used as synonyms)
    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 INNCeralifimod
    D.3.9.1CAS number 891859-12-4
    D.3.9.2Current sponsor codeMSC2430913A or ONO-4641 (to be used as synonyms)
    D.3.9.3Other descriptive nameONO-4641
    D.3.9.4EV Substance CodeSUB30962
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.1
    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 placeboSolution for injection in pre-filled syringe
    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 remitente recidivante
    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 17.0
    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
    The primary objective of this trial is to demonstrate the effect of ONO 4641 versus IFN ? 1a (Avonex) 30 µg on the proportion of subjects, with RMS, who remain qualifying relapse?free during their participation in the trial when the last evaluable subject completes 1 year.
    El objetivo principal de este ensayo es demostrar el efecto de ONO-4641 en
    comparación con interferón (IFN)-?-1a (Avonex) 30 ?g sobre la proporción de
    pacientes con esclerosis múltiple recurrente remitente (EMRR), que continúen sin
    presentar recaídas aptas durante su participación en el ensayo cuando el último
    paciente evaluable complete 1 año
    E.2.2Secondary objectives of the trial
    "To demonstrate the effect of ONO 4641 versus:
    -IFN-?-1a (Avonex) 30 µg on qualifying ARR in subjects with RMS treated over 2 years
    -IFN ? 1a (30 µg) on the number of new or enlarging T2 lesions over 1 and 2 years
    -IFN ? 1a (30 µg) on disability progression over 2 years and disability improvement over 2 years
    Other Secondary Objectives are to demonstrate the effect of ONO 4641 on:
    -additional clinical relapse outcomes (e.g., proportion relapse-free at 2 years) and MRI parameters (e.g., brain atrophy) in subjects with RMS
    -disease-activity-free (DAF) status in subjects with RMS
    -Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT) as measures of cognitive function in subjects with RMS
    To demonstrate the safety and tolerability of treatment with ONO 4641 in RMS subjects"
    Demostrar el efecto de ONO-4641 en comparación con:
    Interferón IFN-beta-1ª (Avonex) 30 ?g sobre la tasa anual de recaídas (TAR) apta en pacientes con EMRR tratados durante 2 años.
    IFN-?beta1a (30 ?g) sobre el número de lesiones nuevas o crecientes en T2 durante 1 y 2 años.
    IFN-beta-1a (30 ?g) sobre la progresión de la discapacidad durante 2 años.

    Otros objetivos secundarios: Demostrar el efecto de ONO-4641 sobre:
    Resultados adicionales de recaída clínica (por ejemplo, la proporción de pacientes sin recaídas a los 2 años) y los parámetros de la resonancia magnética (RM) (por ejemplo, atrofia cerebral) en pacientes con EMRR.
    El estado sin actividad de la enfermedad (SAF) en pacientes con EMRR.
    El test de símbolos y dígitos (SDMT) y la prueba de la adición auditiva consecutiva ritmada (PASAT) como medidas de la función cognitiva en pacientes con EMRR. Demostrar la seguridad y tolerabilidad del tratamiento con ONO en pacientes con EMRR.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    "For inclusion in the trial, all of the following inclusion criteria must be fulfilled:
    A. Signed Informed Consent
    1. Written informed consent obtained prior to the initiation of any protocol-required procedures.
    B. Target Population
    2. Diagnosis of MS as defined by McDonald criteria of 2010
    3. At least 1 documented relapse during the previous year OR at least 2 documented relapses during the previous 2 years prior to Randomization
    4. EDSS (Expanded Disability Status Score) of 0 to 5.5, inclusive
    5. Clinically stable, with no relapse within 30 days prior to Randomization
    C. Age and Reproductive Status
    6. Male or female subjects 18 to 55 years of age
    7. Women of childbearing potential (WOCBP) must use 2 adequate forms of contraception to avoid pregnancy throughout the trial (such as a double barrier method) and for up to 8 weeks after the last dose of IMP in such a manner that the risk of pregnancy is minimized
    NOTE: WOCBP includes any female who has experienced menarche and who has not undergone successful sterilization (such as hysterectomy, bilateral tubal ligation, bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 consecutive months, or women on hormone replacement therapy with documented serum follicle stimulating hormone [FSH] level > 35 mIU/mL). Women using oral, implanted, or injectable contraceptive hormones or using mechanical products (such as an intrauterine device, diaphragm, condoms, etc) to prevent pregnancy; or practicing abstinence; or where the partner is sterile (such as with a vasectomy), must be considered to be of childbearing potential.
    8. WOCBP must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) at the time of Screening AND a negative urine (dipstick) pregnancy test at the time of Randomization
    9. Women must not be breastfeeding
    10. Males must be surgically sterilized or agree to the use of a double-barrier method for the duration of the trial and must agree to refrain from sperm donation for the duration of the trial "
    A. Firma de un consentimiento informado
    1. Consentimiento informado por escrito obtenido antes del inicio de cualquier procedimiento exigido por el protocolo.
    B. Población a la que va dirigido
    2. Diagnóstico de EM según los criterios de McDonald de 2010.
    3. Al menos 1 recaída documentada en el año anterior O por lo menos 2 recaídas documentadas durante los 2 años anteriores a la aleatorización.
    4. Puntuación de la EDSS de 0 a 5,5, inclusive.
    5. Clínicamente estable, sin recaídas durante los 30 días anteriores a la aleatorización.
    C. Edad y estado reproductivo
    6. Edad de los pacientes varones o mujeres entre 18 y 55 años.
    7. Las mujeres en edad fértil (MEF) deben utilizar 2 métodos anticonceptivos adecuados para evitar el embarazo durante todo el ensayo (por ejemplo, un método de barrera doble) y hasta 8 semanas después de la última dosis del PEI, de tal manera que el riesgo de embarazo se reduzca al mínimo.
    NOTA: Las MEF incluyen a cualquier mujer que haya experimentado la menarquia y que no haya sido sometida a una esterilización con éxito (como una histerectomía, ligadura de trompas bilateral, ooforectomía bilateral) o no sea posmenopáusica (definida como amenorrea > 12 meses consecutivos, o mujeres sometidas a terapia de reemplazo hormonal con un nivel de hormona foliculoestimulante [FSH] en suero documentado > 35 mUI/ml). Las mujeres que utilicen hormonas anticonceptivas orales, inyectables o mediante implante, o que utilicen productos mecánicos (por ejemplo, un dispositivo intrauterino, diafragma, condones, etc.) para evitar el embarazo, o que practiquen la abstinencia, o que tengan una pareja estéril (por ejemplo con una vasectomía), deben considerarse en edad fértil.
    8. Las MEF deben presentar un resultado negativo en una prueba de embarazo en suero (sensibilidad mínima de 25 UI/l o unidades equivalentes de gonadotropina coriónica humana [GCH]) en la selección, Y un resultado negativo en una prueba de embarazo en orina (tira reactiva) en el momento de la aleatorización.
    9. Las mujeres no deben estar en período de lactancia.
    10. Los varones deben estar esterilizados quirúrgicamente O aceptar utilizar un método de doble barrera durante el estudio, y deben aceptar abstenerse de donar esperma durante el ensayo.
    E.4Principal exclusion criteria
    "A. Medical History and Concurrent Diseases
    1. Neuromyelitis optica, clinically isolated syndrome, primary or secondary (without relapses) progressive multiple sclerosis
    2. Chronic disease of the immune system other than MS or a known immunodeficiency syndrome
    3. Malignancy
    4. Macular edema or uveitis
    5. Corneal herpes
    6. Inability to undergo slit lamp and OCT assessment
    7. Inability to complete an MRI or contraindications for MRI
    8. History of sudden cardiac arrest
    9. Ischemic cardiac disease including myocardial infarction, stable angina pectoris, unstable angina pectoris
    10. Congestive heart failure New York Heart Association Class III or Class IV
    11. Uncontrolled hypertension
    12. Severe untreated sleep apnea
    13. Cerebrovascular disease in the 6 months prior to Randomization
    14. Symptomatic bradycardia or recurrent syncope
    15. Mobitz Type II second degree or high-grade AV block
    16. Sinoatrial heart block or sick sinus syndrome
    17. Resting HR of < 50 bpm on Screening ECG
    18. Higher risk of symptomatic bradycardia or heart block due to coexisting medical condition or certain concomitant medications
    19. Concurrent therapy with drugs that slow the HR or AV conduction
    20. Family history of long QT syndrome or sudden death
    21. Subjects receiving Class Ia or Class III anti-arrhythmic drugs
    22. Other arrhythmias such as ventricular tachycardia or atrial fibrillation requiring treatment
    23. Uncontrolled diabetes mellitus (Type I or Type II)
    24. Active or latent viral, fungal or other infections, including hepatitis B virus, hepatitis C virus, or known history of human immunodeficiency virus (HIV)-1 or HIV-2
    25. Active or chronic bacterial infection, including untreated tuberculosis, or history of untreated borreliosis (Lyme disease)
    26. Alcohol or drug abuse in the 12 months prior to Randomization
    27. Subject has been vaccinated with live, attenuated vaccines within 2 months prior to Randomization
    28. Renal condition that would preclude the administration of Gd
    29. Respiratory disease, such as pulmonary fibrosis, or asthma requiring chronic daily therapy (exception: resolved childhood asthma)
    30. Abnormal chest X-ray suggestive of active pulmonary disease
    31. Abnormal Pulmonary Function Tests: forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) < 75% or DLCO < 60%
    32. Any other unstable medical conditions (such as congenital heart disease, acute or chronic liver diseases, etc.)
    33. Current uncontrolled or untreated major depressive disorder, and/or at imminent risk of self harm or harm to others
    34. Known hypersensitivity to the trial treatment(s)
    B. Physical and Laboratory Test Findings
    35. Any other abnormal ECG finding, laboratory test result, or vital sign result
    36. Resting HR < 50 bpm based on ECG at Screening, or history of any cardiac conditions that might increase the risk of a significant reduction in HR
    37. Fridericia-corrected QT interval > 450 msec for male subjects and > 470 msec for female subjects on 12-lead ECG
    38. Left bundle branch block
    39. Right bundle branch block with fascicular block (left or right) or any ECG with RBBB and first degree AV block (PR interval > 240 msec) or RBBB with a QRS duration > 140 msec
    40. Intraventricular conduction defect with a QRS duration > 140 msec
    Laboratory exclusions:
    41. ALT or AST > 2 x ULN at Screening
    42. Serum creatinine > 1.5 mg/dL at Screening
    43. Total bilirubin > 1.5 x ULN (except for Gilbert?s disease) at Screening
    44. Lymphocyte count < 800 cells/µL at Screening
    45. WBC < 3,500 cells/µL at Screening
    46. Hemoglobin ? 9 g/dL at Screening
    47. Platelets < 100,000/mm3 at Screening
    48. Hemoglobin A1C > 7.5% at Screening
    C. Allergies
    49. History of allergic reaction to IFN-?-1a (Avonex).
    D. Prohibited Medications and Therapies
    50. Systemic corticosteroids or adrenocorticotropic hormone within 1 month prior to Randomization
    51. Immunoglobulins or plasmapheresis within 3 months prior to Randomization
    52. Cyclophosphamide, cladribine, or mitoxantrone at any time
    53. Immunosuppressive medications such as azathioprine, methotrexate, cyclosporine within 6 months prior to randomization
    54. Any previous therapy with alemtuzumab, ocrelizumab, ofatumumab, rituximab, belimumab, total body irradiation, or bone marrow transplantation
    55. Natalizumab for more than 2 years
    56. Any investigational drug or placebo within 12 weeks prior to Randomization OR > 5 half lives prior to Randomization, whichever is longer
    57. Previous experimental procedures for the treatment of MS, such as treatment for chronic cerebrospinal venous insufficiency, or T-cell / T-cell receptor activation
    58. Any prior exposure to ONO 4641
    59. Prior therapy with fingolimod prior to randomization, or any treatment for MS (excluding corticosteroids, plasmapheresis, immunoglobulins as described above) other than a ?-interferon, glatiramer acetate, BG-12, or teriflunomide"
    A. Neuromiel.ópt, síndr clin aislado, EM 2ria progres o 1ria prog. Hist enf. crónica sist inm, o Síndr.Inmunodef.Hist. o diagn. neopl. malig (incl. cáncer piel excepto
    céls. basales y esc sin recurrencia 5 añ) .Diagn. edema macular o uveítis. Hist. o diagn. herpes córnea. Incapacidad someterse a TCO. Incapacidad completar RM,
    incl., claustrofob, marcapasos, impl. cocleares, dispositivs o clavos
    ferromagnéticos, grapas vasc. intracraneales, bombas insulina, o estimuladores nerv. Hist. parada card. súbita. Cardiopatía isquémica, incl. infarto mioc. (6 meses ant. a aleatorización), angina pecho estable o inestable. Insuf. Card. congestiva Cl.
    III o IV según la NYHA.Hist. o presencia hipert. no controlada. Apnea sueño grave no tratada. Enf. Cerebrovasc. en 6 meses prev a aleatorización. Bradicardia sint.
    o síncope recurrente. Bloq. auriculoventricular de alto grado o 2do gr. Mobitz II. Bloq. card. sinoauricular o síndr. seno enfermo. Frec. cardíaca (FrC) en reposo <
    50 lpm ECG selección. Mayor riesgo de bradicardia sintomática o bloq.o card. debido a coexist de enf. (ed., presencia cardiopatía isq, enf. Cerebrovasc, antecedentes infarto mioc, insuf. Card. congestiva, antecedentes parada card.
    súbita, hipertensión no controlada y apnea sueño grave) o medic. concomitantes (p.ej betabloqueantes, bloqs. canales Ca+). Reciben trtto concomitante medic. q. ralentizan la FrC o la conducción AV (p.ej betabloqueantes, digoxina, o
    bloqueadores canalescalcio q. ralentizan la FrC como diltiazem, verapamilo). Antecedentes familiares síndr. QT largo o muerte súbita. Reciben antiarrítmicos decl. Ia o cl. III. Otras arritmias taquicardia ventr. o fibr. auricular q. requieren tratto.
    Diab. mellitus no controlada (Tipo I o II) (debe estar clín. estable con Hg A1C < 7,5 % selección y mantenerse estable dte. 6 meses antes selección). Infec. virales, fúngicas u otras, activ o latentes, incl. hepatitis B (VHB), hep. C (VHC), o inmunodeficiencia (VIH-1 o VIH-2).Infec. Bact. activa o crónica, incl. tuberc no
    tratada o antecedentes de borreliosis no tratada. Alcoholismo o drogadicción en 12
    meses ant. aleatorización.Vacunado con vac. vivas atenuadas en 2 meses previos aleatorización. Tiene una enf. renal q. impediría la admin. de Gd (p.ej, insuf. renal grave aguda o crónica [tasa filtr.glom. < 30 ml/min/1,73 m2]). Enf. Resp., fibrosis
    pulm. o asma q. requieren terapia diaria (exc. asma infantil resuelta). Radiogr. torax anómala q. indica enf. Pulm. activa y, en opinión del invest., podría exponer a riesgo de AA o interferir evaluaciones seguridad y eficacia. PFP anormales: vol. espiratorio forzado en 1 seg. (VEF1) o capacidad vital forzada (CVF) < 75 % o
    DLCO < 60 % selección. Antecedentes o indicios de otras afecciones inestables
    (como enf. Card. congénitas, enf. hepáticas agudas o crónicas, etc.) q., en opinión
    del invest., podrían ser riesgo de AA o interferir evaluac seguridad y eficacia.Trast.
    depresivo mayor, no controlado o tratado, y/o en riesgo inminente de sufrir
    autolesiones o hacer daño a otros. Hipersensibilidad a trtto del estudio o diluyentes.
    B. Resultado anormal del ECG, pruebas laboratorio o constantes vitales q., a juicio
    del invest., sea significativo, ya q. afectaría a segur pac. o interpretación resultados.
    FrC en reposo < 50 lpm basada en ECG selección, o un Hist. de cualquier afección
    card. q. podría aumentar riesgo reducción significativa de la FrC. Corrección de
    Fridericia intervalo QT (QTcF) > 450 ms varones y > 470 ms mujeres ECG 12 der.
    selección. Bloq. rama izq.Bloq. rama dcha. (BRD) con bloq. fascicular (izq. o dcho)
    o ECG con BRD y bloq. AV de 1er grado (intervalo PR > 240 ms) o BRD con
    duración del QRS > 140 ms. Trast. conducción intraventricular duración QRS>140
    ms. ALT o AS >2 veces límite sup. normalidad (x LSN) selección. Creatinina
    sér.>1,5 mg/dl selecci. Bilirrubina total >1,5 x LSN (exc. enf.Gilbert)
    selecci. Linfocitos <800 cels/?l selección. LEU <3500 cels/?l selección. Hg ? 9
    g/dl selección. Plaq. < 100.000/mm3 selecci. Hg A1C > 7,5 % selección. C. Hist. reacción alérgica IFN-?-1a (Avonex). D. Corticosteroides sist. u hormona
    adrenocorticotrópica 1 mes antes aleatorizac. Inmunoglob. o plasmaféresis 3
    meses aleatorización. Ciclofosfamida, cladribina o mitoxantrona. Inmunodepr:
    azatioprina, metotrexato, ciclofosfamida, cladribina o mitoxantrona. Cualquier trtto
    previo con alemtuzumab, ocrelizumab, ofatumumab, rituximab, belimumab,
    irradiación corp. total o trasplante méd. ósea. Natalizumab por + 2 añ. Fármaco o placebo en
    invest. 12 semanas previas a aleatorización O > 5 semividas antes aleatorización,
    el periodo q. sea más largo. Proced. exp. ant. para EM, como trtto para insuf.
    venosa cerebroespinal crónica, o activación de cels T/receptor cels T. Exposición
    ONO-4641. Terapia fingolimod, o trtto para EM (excl. corticosteroides,
    plasmaféresis e inmunoglobulinas) q. no sea interferón beta, acetato de
    glatirámero, BG-12 (dimetilfumarato) o teriflunomida.
    E.5 End points
    E.5.1Primary end point(s)
    "Proportion of subjects free of qualifying relapse over at least 1 year (48 weeks).
    Relapses confirmed by the Adjudication Committee to meet the definition of qualifying relapse will contribute to the analysis for the primary endpoint."
    Proporción de pacientes que no presentan recaídas aptas durante, al menos, 1 año (48 semanas).
    Las recaídas que, a criterio del Comité de adjudicación, cumplan la definición de recaída apta contribuirán al análisis para el criterio de valoración principal.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1 year
    1 año
    E.5.2Secondary end point(s)
    "? The qualifying Annual Relapse Rate over 2 years
    ? Number of new or enlarging hyperintense lesions on T2 weighted MRI over 1 and 2 years
    ? Time to 3-month confirmed disability progression over 2 years
    ? Time to 3-month confirmed disability improvement over 2 years
    ? Time to 6-month confirmed disability progression and improvement over 2 years
    ? Change from Baseline on the MSFC Z-score at 2 years
    ? Proportion of subjects relapse-free over 2 years
    ? Number and volume of new or persisting T1 Gd-enhancing lesions
    ? T2 lesion volume
    ? Number of combined unique active MRI lesions
    ? Proportion of subjects with no new T1 Gd-enhancing lesions
    ? Proportion of subjects with no new or enlarging T2 lesions
    ? Number of new T1 hypointense lesions
    ? Percent change in brain volume
    ? Proportion of T1 Gd-enhancing lesions evolving into new persistent black holes
    ? Proportion of subjects DAF (Disease Activity Free) (DAF status is defined as a subject having no qualifying relapse, no 3-month sustained change in EDSS, or no active lesions as assessed by MRI [new T1 Gd-enhancing lesions, or new/enlarging T2 lesions])
    ? Change from Baseline in SDMT and PASAT scores
    ? Safety and tolerability of ONO 4641
    "
    ? La TAR apta durante 2 años.
    ? Número de lesiones hiperintensas nuevas o crecientes en las imágenes de RM potenciadas en T2 durante 1 y 2 años.
    ? Tiempo hasta la progresión de la discapacidad confirmada de 3 meses durante los 2 años.
    ? Tiempo hasta la mejoría de la discapacidad confirmada de 3 meses durante los 2 años.
    ? Tiempo hasta la progresión de la discapacidad confirmada de 6 meses durante los 2 años.
    ? Cambio respecto al inicio en la puntuación Z (Z-score) del MSFC a los 2 años.
    ? Proporción de pacientes sin recaídas durante los 2 años.
    ? Número y volumen de lesiones nuevas o persistentes potenciadas con gadolinio (Gd) en T1.
    ? Volumen de la lesión en T2.
    ? Número de lesiones activas únicas combinadas en la RM.
    ? Proporción de pacientes sin lesiones nuevas potenciadas con Gd en T1.
    ? Proporción de pacientes sin lesiones nuevas o crecientes en T2.
    ? Número de nuevas lesiones hipotensas en T1.
    ? Cambio porcentual en el volumen del cerebro.
    ? Proporción de las lesiones potenciadas con Gd en T1 que evolucionan hacia nuevos agujeros negros persistentes.
    ? Proporción de pacientes sin actividad de la enfermedad (SAF) (el estado SAF se define como un paciente que no presenta ninguna recaída apta, ningún cambio sostenido durante 3 meses en la EDSS, o sin ninguna lesión activa según lo evaluado por la RM [lesiones nuevas potenciadas con Gd en T1, o lesiones nuevas/crecientes en T2]).
    ? Cambio respecto al inicio en las puntuaciones de SDMT y PASAT.
    ? Seguridad y tolerabilidad de ONO-4641.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1 and 2 years
    1 y 2 años
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) 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 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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA120
    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
    Belarus
    Belgium
    Brazil
    Bulgaria
    Canada
    Chile
    Colombia
    Czech Republic
    Denmark
    Finland
    France
    Georgia
    Germany
    Hungary
    Israel
    Italy
    Mexico
    Netherlands
    New Zealand
    Peru
    Poland
    Romania
    Russian Federation
    Serbia
    Slovakia
    South Africa
    Spain
    Sweden
    Turkey
    Ukraine
    United Arab Emirates
    United Kingdom
    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
    For administrative and safety reporting purposes, the end of the trial will be defined as the date of the final clinical database lock.
    Para los fines administrativos y de notificación de la seguridad, el final del ensayo
    se definirá como la fecha de cierre final de la base de datos clínicos.
    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 months9
    E.8.9.1In the Member State concerned days23
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days23
    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: 1176
    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 state23
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 482
    F.4.2.2In the whole clinical trial 1176
    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)
    After completing 2 years of treatment, subjects will be offered the opportunity to continue active treatment in an Extension Trial.
    tRAS COMPLETAR 2 AÑOS DE TRATAMIENTO, A LOS PACIENTES SE LES OFRECERÁ LA OPORTUNIDAD DE CONTINUAR CON EL TRATAMIENTO ACTIVO EN UN ESTUDIO DE EXTENSIÓN
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-05-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-05-08
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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