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    Summary
    EudraCT Number:2015-000319-41
    Sponsor's Protocol Code Number:RPC01-3101
    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:2018-05-21
    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 number2015-000319-41
    A.3Full title of the trial
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Oral RPC1063 as Induction and Maintenance Therapy for Moderate to Severe Ulcerative Colitis
    Ensayo de fase 3, multicéntrico, aleatorizado, doble ciego, controlado con placebo, de RPC1063 oral como terapia de inducción y de mantenimiento para la colitis ulcerosa de moderada a grave
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The purpose of this study is to determine whether RPC1063 is safe and effective in the treatment of ulcerative colitis (UC).
    El propósito de este estudio es determinar si RPC1063 es seguro y eficaz en el tratamiento de la colitis ulcerosa (CU).
    A.3.2Name or abbreviated title of the trial where available
    Efficacy and Safety Study of RPC1063 in Ulcerative Colitis
    A.4.1Sponsor's protocol code numberRPC01-3101
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02435992
    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 SponsorCelgene International II Sàrl (CIS II)
    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 supportCelgene International II Sàrl
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationReceptos Services, LLC
    B.5.2Functional name of contact pointTruenorth Study Information Center
    B.5.3 Address:
    B.5.3.1Street Address3033 Science Park Road, Suite 300
    B.5.3.2Town/ citySan Diego, California
    B.5.3.3Post code92121
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18442669299
    B.5.6E-mailtruenorth@quintiles.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.3.9.3Other descriptive name(S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride
    D.3.9.4EV Substance CodeSUB175614
    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 name1.0 mg 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.3.9.3Other descriptive name(S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride
    D.3.9.4EV Substance CodeSUB175614
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Ulcerative colitis
    Colitis ulcerosa
    E.1.1.1Medical condition in easily understood language
    Ulcerative colitis
    Colitis ulcerosa
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10045365
    E.1.2Term Ulcerative colitis
    E.1.2System Organ Class 100000004856
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    INDUCTION THERAPY:
    Demonstrate the efficacy of RPC1063 versus placebo on induction of clinical remission.

    MAINTENANCE THERAPY:
    To demonstrate the efficacy of RPC1063 versus placebo maintenance therapy on clinical remission.
    Período de inducción:
    Demostrar la eficacia de RPC1063 frente a placebo en la inducción de la remisión clínica.

    Período de mantenimiento:
    Demostrar la eficacia de RPC1063 frente a placebo en la remisión clínica.
    E.2.2Secondary objectives of the trial
    INDUCTION THERAPY:
    Demonstrate :
    -the efficacy of RPC1063 versus placebo on induction of clinical response
    -the efficacy of RPC1063 versus placebo on achieving endoscopic improvement
    -the efficacy of RPC1063 versus placebo on achieving histologic remission
    -the safety and tolerability of RPC1063 induction therapy

    MAINTENANCE THERAPY:
    Demonstrate:
    -the efficacy of RPC1063 versus placebo in maintaining clinical response
    -the efficacy of RPC1063 versus placebo on achieving endoscopic improvement
    -the efficacy of RPC1063 versus placebo on durability of clinical remission
    -the efficacy of RPC1063 versus placebo on maintaining clinical remission among patients who achieved remission during induction therapy
    -the efficacy of RPC1063 versus placebo, in achieving corticosteroid-free remission among patients receiving corticosteroids at entry into the Maintenance Period
    -the safety and tolerability of RPC1063 maintenance therapy
    Período de inducción. Demostrar:
    -La eficacia de RPC1063 frente a placebo en la inducción de la respuesta clínica.
    -Eficacia de RPC1063 frente a placebo para lograr la mejora endoscópica.
    -Eficacia de RPC1063 frente a placebo para lograr la remisión histológica.
    -Seguridad y tolerabilidad del tratamiento de inducción con RPC1063.
    Período de mantenimiento. Demostrar:
    -Eficacia de RPC1063 frente a placebo para mantener la respuesta clínica.
    -Eficacia de RPC1063 frente a placebo para lograr la mejora endoscópica.
    -Eficacia de RPC1063 frente a placebo en la durabilidad de la remisión clínica.
    -Eficacia de RPC1063 frente a placebo para mantener la remisión clínica en los pacientes que lograron la remisión durante la terapia de inducción.
    -Eficacia de RPC1063 frente a placebo para lograr la remisión sin corticoesteroides, entre pacientes que reciben corticoesteroides en el ingreso al período de mantenimiento.
    -Seguridad y tolerabilidad de la terapia de mantenimiento con RPC1063.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients aged 18 to 75 years (at screening), inclusive
    2. Have had UC diagnosed at least 3 months prior to first investigational drug administration. The diagnosis should be confirmed by clinical and endoscopic evidence and corroborated by a histopathology report (note: endoscopy and histopathology may be performed at Screening if no prior report is readily available)
    3. Evidence of UC extending >= 15 cm from the anal verge as determined by Baseline endoscopy (flexible sigmoidoscopy or colonoscopy)
    4. Have active UC defined as Mayo score of 6 to 12 inclusive, with endoscopic subscore of >= 2, a rectal bleeding score of >= 1, and a stool frequency score >= 1
    5. Must be currently receiving treatment with at least 1 of the following therapies and must continue on these therapies during Induction:
    - Oral aminosalicylates at a therapeutic dose for their disease (eg, mesalamine, sulfasalazine, olsalazine, balsalazide), with the dose stable
    for at least 3 weeks, prior to Screening endoscopy
    - Prednisone (doses =< 20 mg per day) or equivalent receiving a stable dose for at least 2 weeks prior to Screening endoscopy
    - Budesonide MMX therapy receiving a stable dose for at least 2 weeks prior to Screening endoscopy
    6. Have undergone colonoscopy (or are willing to undergo colonoscopy
    during Screening):
    - within the past 2 years, to screen for dysplasia (unless otherwise recommended by local and national guidelines) if the patient has had
    left-sided colitis of > 12 years duration or total/extensive colitis of > 8 years duration
    - within the past 5 years, to screen for polyps if the patient age is > 45 years
    7. If oral aminosalicylates or corticosteroids have been recently discontinued, they must have been stopped for at least 2 weeks prior to
    the endoscopy used for Baseline Mayo Score
    8. Female patients of childbearing potential: Must agree to practice a highly effective method of contraception throughout the trial until completion of the safety follow-up visit. Highly effective methods of contraception are those that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly. Acceptable methods of birth control in the trial are the following:
    - combined hormonal (oestrogen and progestogen containing) contraception, which may be oral, intravaginal, or transdermal
    - progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injectable, or implantable
    - placement of an intrauterine device (IUD)
    - placement of an intrauterine hormone-releasing system (IUS)
    - bilateral tubal occlusion
    - vasectomised partner
    - sexual abstinence
    Male patients: Must agree to use a latex condom during sexual contact with women of childbearing potential while participating in the study until completion of the safety follow-up visit.
    All patients: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational
    amenorrhoea method are not acceptable methods of contraception. Female condom and male condom should not be used together.
    9. Must provide written informed consent and have the ability to be compliant with the schedule of protocol assessments
    10. Patients must have documentation of positive Varicella zoster virus IgG antibody status or complete Varicella zoster virus vaccination at
    least 30 days prior to randomization
    1. Pacientes de sexo masculino o femenino de 18 a 75 años de edad, inclusive (en el momento de la Selección).
    2. Diagnóstico de CU establecido al menos 3 meses antes del primer día de administración del fármaco en investigación. El diagnóstico debe haberse confirmado por la evidencia clínica y endoscópica, y comprobado mediante un informe de histopatología (Nota: la endoscopia y la histopatología pueden realizarse en la fase de Selección si no está disponible un informe anterior).
    3. Evidencia de CU que se extiende >= 15 cm desde el borde anal, como se determine mediante la endoscopia inicial (sigmoidoscopia flexible o colonoscopia).
    4. CU activa, definida como una puntuación Mayo de 6 a 12 inclusive, con una subpuntuación endoscópica de >= 2, una puntuación de sangrado rectal de >= 1 y una puntuación de frecuencia de las deposiciones de >= 1.
    5. Debe estar recibiendo tratamiento actualmente por lo menos con 1 de las siguientes terapias y debe continuar con estas terapias durante la inducción:
    - Aminosalicilatos orales a una dosis terapéutica para su enfermedad (por ej., mesalamina, sulfasalazina, olsalazina, balsalazida), con la dosis estable durante al menos 3 semanas antes de la endoscopia de la Selección.
    - Prednisona (dosis =< 20 mg por día) o equivalente, con una dosis estable durante al menos 2 semanas antes de la endoscopia de la Selección.
    - Terapia MMX de budesonida, con una dosis estable durante al menos 2 semanas antes de la endoscopia de la Selección.
    6. Haberse sometido a una colonoscopia (o estar dispuestos a someterse a una colonoscopia durante la Selección):
    - en los últimos 2 años, para detectar displasia (a menos que las pautas locales o nacionales recomienden lo contrario), si el paciente ha padecido colitis del lado izquierdo de > 12 años de duración o colitis total/extensa de > de 8 años de duración.
    - en los últimos 5 años, para detectar pólipos si el paciente tiene > 45 años de edad.
    7. Si hace poco se han interrumpido los aminosalicilatos orales o los corticoesteroides, deben haberse suspendido durante al menos 2 semanas antes de la endoscopia usada para establecer la puntuación Mayo inicial.
    8. Las pacientes mujeres con capacidad para concebir:
    Deben acordar el uso de un método anticonceptivo altamente efectivo durante todo el ensayo hasta que se complete la visita de seguimiento de seguridad. Los métodos anticonceptivos altamente eficaces son aquellos que por sí solos o bien combinados con otro tengan como resultado una tasa de fracaso calculada mediante el Índice de Pearl menor que el 1% anual al utilizarse de manera sistemática y adecuada. Los métodos anticonceptivos aceptables en el ensayo son los siguientes:
    - anticonceptivos hormonales combinados (con estrógeno y progesterona), que pueden ser orales, intravaginales o transdérmicos
    - anticonceptivos hormonales con progesterona únicamente asociados con la inhibición de la ovulación, que pueden ser orales, inyectables o implantables
    - colocación de un dispositivo intrauterino (DIU)
    - colocación de un sistema intrauterino liberador de hormonas (SIU)
    - oclusión tubaria bilateral
    - vasectomía de la pareja
    - abstinencia sexual
    Los pacientes varones:
    Deben aceptar el uso de un condón de látex durante el contacto sexual con mujeres con capacidad de concebir durante su participación en el estudio y hasta haber finalizado la visita de seguimiento de seguridad.
    Todos los pacientes:
    La abstinencia periódica (método calendario, método sintotérmico, método post-ovulación), la marcha atrás (coitus interruptus), el uso de espermicidas únicamente, y el método de la amenorrea de la lactancia no se consideran métodos anticonceptivos aceptables. No deben utilizarse condones femeninos y condones masculinos juntos.
    9. Deben proporcionar un consentimiento informado escrito y tener la capacidad de cumplir con el calendario de evaluaciones del protocolo.
    10. Los pacientes deben tener documentada la presencia de anticuerpos inmunoglobulina G (IgG) positivos para el virus varicela-zóster (VZV) o completar la vacuna contra el VZV por lo menos 30 días antes de la aleatorización.
    E.4Principal exclusion criteria
    Exclusions Related to General Health:
    1. Have severe extensive colitis as evidenced by:
     - Physician judgment that the patient is likely to require colectomy or ileostomy within 12 weeks of Baseline
     - Current or recent (within 3 months) evidence of fulminant colitis, toxic megacolon, or bowel perforation
    2. Diagnosis of Crohn’s disease or indeterminate colitis or the presence or history of a fistula consistent with Crohn’s disease or microscopic colitis or radiation colitis or ischemic colitis
    3. Have positive stool examination for pathogens (ova and parasites, bacteria) or positive test for toxin producing Clostridium difficile (C. difficile) at Screening. PCR (polymerase chain reaction) examination of the stool for C. difficile may be used to exclude false positives. If positive, patients may be treated and retested. Documentation of a negative test result for pathogens (ova and parasites, bacteria) is required within 60 days of Day 1
    4. Pregnancy, lactation, or a positive serum β-human chorionic gonadotropin (β-hCG) measured during Screening
    5. Clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, psychiatric, or other major systemic disease making implementation of the protocol or interpretation of the trial difficult or that would put the patient at risk by participating in the trial
    6. Clinically relevant cardiovascular conditions, including history or presence of:
    - 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
     - Prolonged Fridericia’s corrected QT interval (QTcF; QTcF > 450 msec for males, > 470 msec for females), or at additional risk for QT interval prolongation (eg, hypokalemia, hypomagnesemia, congenital long-QT syndrome)
     - Resting HR < 55 bpm when taking vital signs as part of a physical exam at Screening
    7. History of diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with glycosylated Hb
    HbA1c) > 9% , or diabetic patients with significant comorbid conditions such as retinopathy or nephropathy
    8. History of uveitis (within the last year) or macular edema
    9. 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 and minor skin infections]) or any major episode of infection that required hospitalization or treatment with intravenous antibiotics within 30 days of Screening or oral antibiotics within 14 days of Screening
    10. Recurrent or chronic infection (eg, hepatitis A, B, or C, human immunodeficiency virus (HIV); recurrent urinary tract are allowed.
    11. History of cancer, including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin or uterine cervix that have been excised and resolved) or colonic mucosal dysplasia
    12. History of alcohol or drug abuse within 1 year prior to randomization
    13. History of or currently active primary or secondary immunodeficiency
    Exclusions Related to Medications:
    14. History of treatment with a biologic agent within 8 weeks or 5 elimination half-lives (whichever is less) of that agent prior to randomization
    15. History of treatment with an investigational agent within 5 elimination half-lives of that agent prior to randomization
    16. History of treatment with topical rectal 5-aminosalicylic acid or topical rectal steroids within 2 weeks of Screening endoscopy or anti-motility medications (such as diphenoxylate/atropine)
    during Screening
    17. Receipt of a live vaccine within 4 weeks prior to randomization
    18. Previous treatment with lymphocyte-depleting therapies (eg, Campath, anti-CD4, cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body irradiation, bone marrow
    ransplantation, alemtuzumab, daclizumab)
    19. Have had treatment with cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 16 weeks of Screening or tofacitinib within 2 weeks of Screening
    20. Previous treatment with D-penicillamine, leflunomide, or thalidomide
    21. Previous treatment with natalizumab or fingolimod
    22. History of treatment with intravenous immune globulin (IVIg) or plasmapheresis within 3 months
    prior to randomization
    23. Planned concurrent treatment with immunosuppressive agents (eg, azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate) after randomization. Patients receiving AZA, 6-MP, or methotrexate at Screening must discontinue treatment with these agents prior to randomization
    24.-36. criteria not entered here due to lack of characters- all exclusion criteria are available in Protocol
    1. Tener colitis extensa grave, evidenciada por:
    - Criterio médico de que el paciente probablemente requiera una colectomía o una ileostomía en 12 semanas desde el nivel inicial.
    - Evidencia actual o reciente (3 meses) de colitis fulminante, megacolon tóxico o perforación intestinal.
    2. Diagnóstico de enfermedad de Crohn o colitis indeterminada o presencia o antecedentes de una fístula coincidente con la enfermedad de Crohn o con colitis microscópica o colitis por radiación o colitis isquémica
    3. Tener examen positivo en las deposiciones de patógenos (huevos y parásitos, bacterias) o prueba con resultado positivo de toxinas producidas por C. difficile en la Selección. El examen PCR de las heces para C. difficile se puede utilizar para excluir falsos positivos. Si diese positivo, los pacientes se pueden tratar y volver a evaluar. Es necesario documentar los resultados negativos de los exámenes de patógenos en los 60 días anteriores al día 1
    4. Embarazo, lactancia o medición positiva de β-hCG en suero, medida durante la Selección
    5. Enfermedad hepática, neurológica, pulmonar, oftalmológica, endocrina, psiquiátrica o de otro sistema importante, que sea clínicamente relevante, y que dificulte la implementación del protocolo o la interpretación del ensayo o que ponga en riesgo al paciente por participar en el ensayo
    6. Afecciones cardiovasculares clínicamente relevantes, incluidos antecedentes o presencia de lo siguiente:
    - Manifestación reciente (últimos 6 meses) de infarto de miocardio, angina de pecho inestable, accidente cerebrovascular, accidente isquémico transitorio, insuficiencia cardíaca con descompensación que requirió hospitalización, insuficiencia cardíaca de clase III/IV, síndrome del seno enfermo o apnea del sueño grave sin tratar
    - Prolongación del intervalo QT corregido por Fridericia (QTcF; QTcF > 450 mseg para hombres, > 470 mseg para mujeres) o en riesgo adicional de prolongación del intervalo QT (ej., hipopotasemia, hipomagnesemia, síndrome de QT largo congénito).
    - FC <55 lpm en reposo cuando se miden las constantes vitales como parte de una exploración física en la Selección.
    7. Antecedentes de diabetes mellitus tipo 1 o tipo 2 no controlada, con HbA1c >9 % o pacientes diabéticos con afecciones concomitantes importantes como retinopatía o nefropatía.
    8. Antecedentes de uveítis (último año) o edema macular
    9. Infección bacteriana, vírica, fúngica o micobacteriana activa y conocida u otra infección (incluida tuberculosis o enfermedad micobacteriana atípica o cualquier otro episodio importante de infección que requirió hospitalización o tratamiento con antibióticos intravenosos en los 30 días previos a la Selección o antibióticos orales en los 14 días previos a la Selección
    10. Infección recurrente o crónica (ej., hepatitis A, B o C, VIH). Se permiten las infecciones recurrentes de las vías urinarias
    11. Antecedentes de cáncer, incluidos tumores sólidos y neoplasias malignas hematológicas (excepto carcinomas de células basales y escamosos in situ de la piel o del cuello uterino que se han extirpado o resuelto) o displasia de la mucosa colónica
    12. Antecedentes de abuso de drogas o alcoholismo, según la opinión del investigador, en el lapso de 1 año antes de la aleatorización
    13. Antecedentes de inmunodeficiencia primaria o secundaria activa actualmente
    Exclusiones relacionadas con los medicamentos:
    14. Antecedentes de tratamiento con un fármaco biológico en 8 semanas o 5 semividas de eliminación de dicho agente (lo que sea menor) antes de la aleatorización
    15. Antecedentes de tratamiento con un fármaco experimental en un plazo de 5 semividas de eliminación de dicho agente antes de la aleatorización
    16. Antecedentes de tratamiento tópico rectal con ácido 5-aminosalicílico o esteroides en 2 semanas antes de la endoscopia de Selección o medicamentos contra la motilidad (como difenoxilato/atropina) durante la Selección
    17. Haber recibido una vacuna de virus vivo en 4 semanas antes de la aleatorización.
    18. Tratamiento previo con terapias destructoras de linfocitos (por ej., Campath, anti-CD4, cladribina, rituximab, ocrelizumab, ciclofosfamida, mitoxantrona, irradiación de todo el cuerpo, trasplante de médula ósea, alemtuzumab, daclizumab).
    19. Haber recibido tratamiento con ciclosporina, tacrolimus, sirolimus o MMF en 16 semanas antes de la Selección o tofacitinib en 2 semanas antes de la Selección.
    20. Tratamiento previo con D-penicilamina, leflunomida o talidomida.
    21. Tratamiento previo con natalizumab o fingolimod.
    22. Antecedentes de tratamiento con inmunoglobulina intravenosa (IVIg) o plasmaféresis en 3 meses antes de la aleatorización.
    23. Tratamiento concomitante planificado con agentes inmunosupresores después de la aleatorización. Los pacientes que reciben AZA o 6-MP o metotrexato en la Selección deben interrumpir el tratamiento con estos agentes antes de la aleatorización
    24.-36. criterios no incluidos aquí por falta de espacio; disponibles en el protocolo
    E.5 End points
    E.5.1Primary end point(s)
    The efficacy endpoints will be formally examined with statistical hypothesis tests conducted on the efficacy results obtained from patients randomized and dosed in Cohort 1. Cohort 2 is open-label and does not contain a control group

    INDUCTION PHASE Cohort 1
    Primary Efficacy Endpoint:
    - The proportion of patients in clinical remission at Week 10.

    INDUCTION PHASE Cohort 2
    Cohort 2 is open label; therefore no formal analysis of efficacy endpoints will be conducted.
    All efficacy endpoints will be summarized and described without hypothesis testing.

    MAINTENANCE PHASE
    Primary Efficacy Endpoint:
    - The proportion of patients in clinical remission at 52 weeks
    Los puntos finales de eficacia se examinarán formalmente con pruebas de hipótesis estadísticas realizadas sobre los resultados de eficacia obtenidos de pacientes asignados al azar y dosificados en la Cohorte 1. La cohorte 2 es de etiqueta abierta y no contiene un grupo de control.

    FASE DE INDUCCIÓN Cohorte 1
    Criterio principal de valoración de la eficacia:
    - Proporción de pacientes en remisión clínica en la semana 10.

    FASE DE INDUCCIÓN Cohorte 2
    - La cohorte 2 es abierta, por lo que no se realizará un análisis formal de los criterios de valoración de la eficacia en la cohorte 2.
    - Todos los criterios de valoración de la eficacia mencionados arriba se resumirán y se describirán sin análisis de hipótesis.

    FASE DE MANTENIMIENTO:
    Criterio principal de valoración de la eficacia:
    - Proporción de pacientes en remisión clínica a las 52 semanas
    E.5.1.1Timepoint(s) of evaluation of this end point
    At 10 weeks (Induction Visit I4/Week 10)
    At 52 weeks (Maintenance Visit M5/Week 42)
    A las 10 semanas (visita de inducción I4 / Semana 10)
    A las 52 semanas (visita de mantenimiento M5 / semana 42)
    E.5.2Secondary end point(s)
    INDUCTION PHASE
    Key Secondary Efficacy Endpoints:
    - The proportion of patients with a clinical response at Week 10
    - The proportion of patients with endoscopic improvement at Week 10
    - The proportion of patients with mucosal healing at Week 10

    MAINTENANCE PHASE
    Key Secondary Efficacy Endpoints:
    - The proportion of patients with a clinical response at 52 weeks
    - The proportion of patients with endoscopic improvement at 52 weeks
    - The proportion of patients with durable clinical remission
    - The proportion of patients in clinical remission at 52 weeks in the subset of patients who were
    in remission at Week 10
    - The proportion of patients with corticosteroid-free remission
    - The proportion of patients with mucosal healing at 52 weeks

    OTHER ENDPOINTS
    Safety
    Pharmacokinetic and pharmacodynamic
    FASE DE INDUCCIÓN:
    Criterios secundarios clave de valoración de la eficacia:
    - Proporción de pacientes con respuesta clínica en la semana 10
    - Proporción de pacientes con mejora endoscópica en la semana 10
    - Proporción de pacientes con cicatrización de la mucosa en la semana 10.

    FASE DE MANTENIMIENTO:
    Criterios secundarios clave de valoración de la eficacia:
    - Proporción de pacientes con respuesta clínica a las 52 semanas
    - Proporción de pacientes con mejora endoscópica a las 52 semanas
    - Proporción de pacientes con remisión clínica duradera
    - Proporción de pacientes en remisión clínica a las 52 semanas en el subconjunto de pacientes que estaban en remisión en la semana 10
    - Proporción de pacientes con remisión sin corticoesteroides
    - Proporción de pacientes con cicatrización de la mucosa a las 52 semanas

    OTROS CRITERIOS DE VALORACIÓN
    Seguridad
    Farmacocinética y farmacodinámica
    E.5.2.1Timepoint(s) of evaluation of this end point
    At 10 weeks (Induction Visit I4/Week 10)
    At 52 weeks (Maintenance Visit M5/Week 42)
    From the list of Other efficacy endpoints during maintenance phase (not primary or secondary) some endpoints are evaluated at 28 weeks (Maintenance Visit M3/Week 18), 40 weeks (Maintenance Visit M3/Week 30) and 52 weeks (Maintenance Visit M3/Week 42).
    A las 10 semanas (Visita de inducción I4 / Semana 10)
    A las 52 semanas (Visita de mantenimiento M5 / semana 42)
    De la lista de Otros puntos finales de eficacia durante la fase de mantenimiento (no primaria o secundaria), algunos puntos finales se evalúan a las 28 semanas (visita de mantenimiento M3 / semana 18), 40 semanas (visita de mantenimiento M3 / semana 30) y 52 semanas (visita de mantenimiento M3 / Semana 42).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic 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 Yes
    E.8.1.7.1Other trial design description
    2 fases: Inducción (cohorte1:control aleat. placebo, cohorte2:abierta); Mantenimiento(contr.placebo)
    2 phases. Induction (Cohort1: Random PlaceboContr; Cohort2: OpenLabel); Maintenance (PlaceboContr)
    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 trial4
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA100
    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
    Australia
    Austria
    Belarus
    Belgium
    Bulgaria
    Canada
    Czech Republic
    France
    Germany
    Greece
    Hungary
    Israel
    Italy
    Korea, Republic of
    Latvia
    Netherlands
    New Zealand
    Poland
    Russian Federation
    Slovakia
    South Africa
    Spain
    Ukraine
    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
    LVLS
    Última visita del último paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    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 months4
    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: 873
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 27
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 427
    F.4.2.2In the whole clinical trial 900
    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)
    Patients may roll-over into an open-label extension study.
    Los pacientes pueden pasar a un estudio de extensión abierto.
    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 Decision2018-07-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-06
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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