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    Summary
    EudraCT Number:2014-001634-28
    Sponsor's Protocol Code Number:MDV3100-13
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-04-27
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2014-001634-28
    A.3Full title of the trial
    A Phase 3, Randomized, Efficacy and Safety Study of Enzalutamide Plus Leuprolide, Enzalutamide Monotherapy, and Placebo Plus Leuprolide in Men
    With High-Risk Nonmetastatic Prostate Cancer Progressing After Definitive Therapy.
    Estudio aleatorizado de fase III de la eficacia y la seguridad de la enzalutamida con leuprolida, de la monoterapia con enzalutamida y del placebo con
    leuprolida, en hombres que padecen una progresión del cáncer de próstata de alto riesgo, no metastatizante, tras el tratamiento definitivo.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An international study to evaluate the safety and effectiveness of enzalutamide plus leuprolide, enzalutamide alone, and leuprolide alone in men with high-risk nonmetastatic prostate cancer progressing after definitive therapy.
    Estudio interncional para evaluar la seguridad y eficacia de enzalutamida más leuprolida, enzalutamida solo, y leuprolida solo, en hombres que padecen una progresión del cáncer de próstata de alto riesgo, no metastatizante, tras el tratamiento definitivo.
    A.4.1Sponsor's protocol code numberMDV3100-13
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02319837
    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 SponsorMedivation, 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 supportMedivation, Inc.
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportAstellas Pharma Global Development, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedivation, Inc.
    B.5.2Functional name of contact pointMedical Officer
    B.5.3 Address:
    B.5.3.1Street Address525 Market Street, 36th Floor
    B.5.3.2Town/ citySan Francisco, CA
    B.5.3.3Post code94105
    B.5.3.4CountryUnited States
    B.5.4Telephone number14155433470
    B.5.5Fax number14155433411
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Xtandi
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma Europe B.V.
    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 nameXtandi (enzalutamide)
    D.3.2Product code MDV3100
    D.3.4Pharmaceutical form Capsule, soft
    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 INNENZALUTAMIDE
    D.3.9.1CAS number 915087-33-1
    D.3.9.2Current sponsor codeMDV3100
    D.3.9.4EV Substance CodeSUB77412
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 Eligard 22.5 mg
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma Co. Ltd
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 nameEligard 22.5 mg (leuprorelin acetate)
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLEUPRORELIN ACETATE
    D.3.9.1CAS number 74381-53-6
    D.3.9.3Other descriptive nameLEUPROLIDE ACETATE
    D.3.9.4EV Substance CodeSUB02900MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number22.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, soft
    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
    Patients with high-risk nonmetastatic prostate cancer progressing after definitive therapy (radical prostatectomy or radiotherapy or both).
    Pacientes con cáncer de próstata no metastásico de alto riesgo progresan después de la terapia definitiva (prostatectomía radical o radioterapia o ambas)
    E.1.1.1Medical condition in easily understood language
    Prostate Cancer
    Cáncer de próstata
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10060862
    E.1.2Term Prostate cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate efficacy, as measured by metastasis-free survival (MFS)
    Evaluar la eficacia, medida por la supervivencia sin metástasis (MFS).
    E.2.2Secondary objectives of the trial
    ? To evaluate efficacy, as measured by the following:
    ? Key protected secondary endpoints:
    * Overall survival
    * Proportion of patients per group who remain treatment-free 2 years after suspension of study drug treatment at week 37 due to undetectable prostate-specific antigen (PSA)
    * Time to castration resistance
    ? Proportion of patients per group with undetectable PSA 2 years after suspension of study drug treatment at week 37 due to undetectable PSA
    ? Proportion of patients per group with undetectable PSA at 36 weeks on study drug
    ? Prostate cancer-specific survival
    ? Time to resumption of any hormonal therapy following suspension at week 37 due to undetectable PSA
    ? Time to first symptomatic skeletal event
    ? Time to metastasis
    ? Time to clinically relevant pain
    ? Quality of life
    ? To evaluate safety
    ? Criterios secundarios protegidos clave:
    - Supervivencia global
    - Proporción de pacientes por grupo que siguen sin recibir tratamiento dos años después de la suspensión del tratamiento con el fármaco investigado en la semana 37 debido a que el antígeno prostático específico (PSA) es indetectable;
    - Tiempo hasta la resistencia a la castración
    ? Proporción de pacientes por grupo con PSA indetectable dos años después de la suspensión del tratamiento con el fármaco investigado en la semana 37 debido a que el PSA es indetectable
    ? Poporción de pacientes por grupo con PSA indetectable en la semana 36 con el fármaco investigado
    ? Supervivencia asociada al cáncer de próstata
    ? Tiempo hasta la reanudación de cualquier hormonoterapia tras la suspensión en la semana 37 debido a que el PSA es indetectable
    ? Tiempo hasta el primer acontecimiento óseo sintomático
    ? Tiempo hasta la metástasis
    ? Tiempo hasta padecer dolor clínicamente relevante
    ? la calidad de vida
    - Evaluar la seguridad
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age 18 years or older and willing and able to provide informed consent.
    2. Histologically or cytologically confirmed adenocarcinoma of the prostate at initial biopsy, without neuroendocrine differentiation, signet cell, or small cell features.
    3. Prostate cancer initially treated by radical prostatectomy or radiotherapy (including brachytherapy) or both, with curative intent.
    4. PSA doubling time ? 9 months as calculated by the sponsor.
    5. Screening PSA ? 2.0 ng/mL for patients who had radical prostatectomy as primary treatment for prostate cancer or ? 5.0 ng/mL and greater than or equal to the nadir + 2 ng/mL for patients who had radiotherapy as primary treatment for prostate cancer.
    6. Serum testosterone ? 150 ng/dL (5.2 nmol/L) at screening.
    7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening.
    8. Estimated life expectancy of ? 12 months.
    9. Able to swallow the study drug and comply with study requirements including independently completing study questionnaires.
    10. Throughout study, the patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (1 of which must include a condom as a barrier method of contraception) from screening through 3 months after the last dose of study drug or per local guidelines where these require additional description of contraceptive methods. Two acceptable methods of birth control thus include the following:
    ? Condom (barrier method is required)
    AND
    ? One of the following is required:
    ? Established and ongoing use of oral, injected, or implanted hormonal method of contraception by the female partner
    ? Placement of an intrauterine device or intrauterine system by the female partner
    ? Additional barrier method including contraceptive sponge and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female partner
    ? Tubal ligation in the female partner performed at least 6 months before screening
    ? Vasectomy or other procedure resulting in infertility (eg, bilateral orchiectomy), performed at least 6 months before screening
    11. Throughout the study, the patient must use a condom if having sex with a pregnant woman.
    12. Must agree not to donate sperm from first dose of study drug through 3 months after the last dose of study drug.
    1. Tener 18 años o más y estar dispuestos a prestar su consentimiento informado, además de disponer de capacidad para hacerlo.
    2. Padecer adenocarcinoma de la próstata confirmado en la biopsia inicial mediante histología o citología, sin diferenciación neuroendocrina, células en sello ni características microcíticas.
    3. Cáncer de próstata tratado inicialmente con prostatectomía radical, con radioterapia (incluida la braquiterapia) o con ambos tratamientos con intención curativa.
    4. Tiempo de duplicación del PSA ? 9 meses, calculado por el promotor.
    5. PSA del periodo de selección ? 2,0 ng/ml en el caso de los pacientes que se hayan sometido a una prostatectomía radical como tratamiento principal para el cáncer de próstata o ? 5,0 ng/ml y mayor o igual que el punto más bajo + 2 ng/ml en el caso de los pacientes que hayan recibido radioterapia como tratamiento principal para el cáncer de próstata.
    6. Testosterona en el suero ? 150 ng/dl (5,2 nmol/l) durante la selección.
    7. Estado funcional según la escala ECOG (Eastern Cooperative Oncology Group) de 0 o 1 durante la selección.
    8. Esperanza de vida estimada ? 12 meses.
    9. Ser capaz de ingerir el fármaco investigado y cumplir los requisitos del estudio, incluida la realización de los cuestionarios de forma independiente.
    10. Durante todo el estudio, el paciente y su compañera, si tiene capacidad reproductiva, deben usar dos métodos anticonceptivos aceptables (uno de los cuales debe ser un preservativo, que se utilizará como método anticonceptivo de barrera) desde el periodo de selección hasta los tres meses siguientes a la última dosis del fármaco investigado o de acuerdo con las directrices locales cuando estas precisen una descripción adicional de los métodos anticonceptivos. Los dos métodos anticonceptivos aceptables pueden ser:
    ? un preservativo (es obligatorio un método de barrera); Y
    ? uno de los siguientes métodos: ? el uso probado y presente de un método hormonal anticonceptivo oral, inyectado o implantado por parte de la compañera del paciente; ? la colocación de un sistema o dispositivo intrauterino por parte de la compañera del paciente;
    ? otro método de barrera, incluido el uso de una esponja anticonceptiva y un capuchón oclusivo (diafragma o capuchones cervicales o en bóveda) con espuma, gel, película,crema o supositorios espermicidas, por parte de la compañera del paciente;
    ? ligadura de trompas; la compañera del paciente debe haberse sometido a esta intervención al menos 6 meses antes de la selección;
    ? vasectomía o cualquier otra intervención que ocasione infertilidad (por ejemplo, orquiectomía bilateral); dichas intervenciones deben haberse efectuado al menos 6 meses antes de la selección.
    11. Durante todo el estudio, el paciente debe usar un preservativo si mantiene relaciones sexuales con una mujer embarazada.
    12. No debe donar semen desde el momento en que reciba la primera dosis del fármaco investigado hasta tres meses después de la administración de la última dosis de dicho fármaco.
    E.4Principal exclusion criteria
    1. Prior or present evidence of distant metastatic disease as assessed by computed tomography (CT) or magnetic resonance imaging (MRI) or chest x-ray for soft tissue disease and whole-body radionuclide bone scan for bone disease. Patients with soft tissue pelvic disease may be eligible if lesions do not qualify as target lesions (eg, lymph nodes below aortic bifurcation are permissible if the short axis of the largest lymph node is < 15 mm). If the screening bone scan shows a lesion suggestive of metastatic disease, the patient will be eligible only if a second imaging modality (plain film, CT, or MRI) does not show bone metastasis. If the imaging results are equivocal or consistent with metastasis, the patient is not eligible for enrollment.
    2. Prior hormonal therapy other than neoadjuvant/adjuvant therapy to treat prostate cancer ? 36 months in duration and ? 9 months before randomization.
    3. Prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone acetate, or enzalutamide for prostate cancer.
    4. Prior systemic biologic therapy, including immunotherapy, for prostate cancer.
    5. Major surgery within 4 weeks before randomization date.
    6. Treatment with 5-? reductase inhibitors (finasteride, dutasteride) within 4 weeks of randomization.
    7. For patients who had a prior prostatectomy, a suitable candidate for salvage radiotherapy as determined by the investigator in consideration of appropriate guidelines (eg, American Society for Radiation Oncology / American Urological Association [ASTRO/AUA]; European Association of Urology [EAU]).
    8. Participation in a clinical study of an investigational agent that inhibits the androgen receptor or androgen synthesis (eg, TAK-700, ARN-509, ODM-201); patients who received placebo are allowed.
    9. Use of any other investigational agent within 4 weeks before randomization date.
    10. Known or suspected brain metastasis or active leptomeningeal disease.
    11. History of another invasive cancer within 3 years before screening, with the exception of fully treated cancers with a remote probability of recurrence. The medical monitor and investigator must agree that the possibility of recurrence is remote.
    12. Absolute neutrophil count < 1500/?L, platelet count < 100,000/?L, or hemoglobin < 10 g/dL (6.2 mmol/L) at screening. NOTE: May not have received any growth factors or blood transfusions within 7 days before the hematology values obtained at screening.
    13. Total bilirubin ? 1.5-times the upper limit of normal (except patients with documented Gilbert?s disease), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ? 2.5-times the upper limit of normal at screening.
    14. Creatinine > 2 mg/dL (177 ?mol/L) at screening.
    15. Albumin < 3.0 g/dL (30 g/L) at screening.
    16. History of seizure or any condition that may predispose to seizure (eg, prior cortical stroke or significant brain trauma). History of loss of consciousness or transient ischemic attack within 12 months before randomization.
    17. Clinically significant cardiovascular disease including the following:
    - Myocardial infarction within 6 months before screening
    - Unstable angina within 3 months before screening
    - New York Heart Association class III or IV congestive heart failure or a history of New York Heart Association class III or IV congestive heart failure unless a screening echocardiogram or multigated acquisition scan performed within 3 months before the randomization date demonstrates a left ventricular ejection fraction ? 45%
    - History of clinically significant ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
    - History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
    - Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening
    - Bradycardia as indicated by a heart rate of ? 45 beats per minute on the screening electrocardiogram (ECG)
    - Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg at screening
    18. Gastrointestinal disorder affecting absorption.
    19. Hypersensitivity reaction to enzalutamide or any of the capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene.
    20. Contraindication to the use of leuprolide, such as a previous hypersensitivity reaction to an LHRH analogue or any of the excipients in the leuprolide injection.
    21. Ongoing drug or alcohol abuse as per investigator judgment.
    22. Any concurrent disease, infection, or comorbid condition that interferes with the ability of the patient to participate in the study, which places the patient at undue risk, or complicates the interpretation of data, in the opinion of the investigator or medical monitor.
    1.Indicios de enfermedad metastásica a distancia, evaluada mediante TAC, RMN o radiografía torácica casos de la enfermedad de los tejidos blandos y mediante gammagrafía ósea de cuerpo entero con radionúclidos en casos de enfermedad ósea. Se consideran aptos los pacientes con enfermedad pélvica de los tejidos blandos si las lesiones no están clasificadas como lesiones objetivo fático. Si la gammagrafía ósea obtenida durante el periodo de selección muestra una lesión que sugiere una enfermedad metastásica, el paciente solo será apto si una segunda modalidad exploratoria por imágenes (radiografía simple, TAC o RMN) no muestra una metástasis ósea. Si los resultados de la exploración por imágenes son equívocos o compatibles con la metástasis, el paciente no será apto para participar.
    2. Hormonoterapia anterior distinta al tratamiento neoadyuvante/adyuvante para tratar el cáncer de próstata de ? 36 meses de duración y ? 9 meses antes de la aleatorización.
    3. Tto anterior con quimioterapia citotóxica, aminoglutetimida, ketoconazol, acetato de abiraterona o enzalutamida para el cáncer de próstata.
    4. Tto biológico sistémico anterior, incluida la inmunoterapia, para el cáncer de próstata.
    5. Intervención quirúrgica mayor en las 4 semanas previas a la aleatorización.
    6. Tto con inhibidores de la 5-? reductasa en las 4 semanas previas a la aleatorización.
    7. En el caso de pacientes que se hayan sometido a una prostatectomía, un candidato adecuado para la radioterapia de rescate, según determine el investigador en función de las directrices de la Asociación Estadounidense de Radiooncología (ASTRO), Asociación Estadounidense de Urología (AUA) o Asociación Europea de Urología (EAU).
    8. Participación en el estudio clínico de un fármaco en fase de investigación que inhiba la síntesis de andrógenos o del receptor de andrógenos, admiten pacientes que recibieron placebo.
    9. Uso de cualquier otro agente en fase de investigación 4 semanas previas a la aleatorización.
    10. Confirmación o sospecha de metástasis cerebral o enfermedad leptomeníngea activa.
    11. Antecedentes de otro cáncer invasivo en los 3 años anteriores con excepción del cáncer tratado con una escasa probabilidad de recurrencia.
    El monitor y el IP estarán de acuerdo que la posibilidad de recurrencia es escasa.
    12. Recuento absoluto de neutrófilos < 1500/?l, recuento de plaquetas < 100.000/?l o hemoglobina < 10 g/dl (6,2 mmol/l) durante la selección.
    13. Bilirrubina total ? 1,5 veces el límite superior de la normalidad (excepto pac con síndrome de Gilbert comprobado), alanina aminotransferasa o aspartato aminotransferasa (AST) ? 2,5 veces el límite superior de la normalidad durante la selección.
    14. Creatinina > 2 mg/dl (177 ?mol/l) durante la selección.
    15. Albúmina < 3,0 g/dl (30 g/l) durante la selección.
    16. Antecedentes de crisis convulsivas o de trastornos que predispongan a crisis convulsivas
    Antecedentes de pérdida de conciencia o de accidente isquémico transitorio en los 12 meses previos a la aleatorización.
    17. Enfermedad cardiovascular clínicamente importante, incluidas las siguientes: Infarto de miocardio en los 6 meses anteriores a la selección
    Angina inestable en los 3 meses anteriores a la selección, Insuficiencia cardíaca congestiva de clase II o IV, Asociación Cardiaca de Nueva York o antecedentes de insuficiencia cardiaca congestiva de clase II o IV según la NYHA, a menos que un ecocardiograma obtenido durante la selección o una gammagrafía con adquisición sincronizada múltiple efectuada en los 3 meses anteriores a la fecha de aleatorización muestren una fracción de eyección del ventrículo izquierdo ? 45 % Antecedentes de arritmias ventriculares clínicamente significativas, Antecedentes de bloqueo cardiaco de segundo grado, Mobitz II, o de tercer grado sin un marcapasos permanente implantado. Hipotensión, indicada por una presión arterial sistólica < 86 mm Hg durante la selección
    - Bradicardia, por una frecuencia cardiaca de ? 45 latidos por minuto en el electrocardiograma (ECG) obtenido durante selección. Hipertensión incontrolada, por un mínimo de dos mediciones consecutivas de la presión arterial que muestren una presión arterial sistólica > 170 mm Hg o una presión arterial diastólica > 105 mm Hg durante la selección
    18. Trastorno gastrointestinal que afecte a la absorción.
    19. Reacción de hipersensibilidad a la enzalutamida o a alguno de los componentes de la cápsula, incluidos Labrasol, butilhidroxianisol y butilhidroxitolueno.
    20. Contraindicación al uso de leuprolida, como reacción de hipersensibilidad anterior a un análogo del LHRH o a cualquier excipientes en el inyectable de leuprolida.
    21. Abuso de drogas o alcohol según criterio del IP.
    22. Cualquier enfermedad o infección concurrente, o afección comórbida, que interfiera en la capacidad del paciente para participar , exponga al paciente a un riesgo innecesario o complique la interpretación de los datos, en opinión del investigador o del monitor.
    E.5 End points
    E.5.1Primary end point(s)
    Metastasis free survival (MFS)
    supervivencia sin metástasis (MFS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    MFS is defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death on study (death within 168 days after permanent treatment discontinuation), whichever occurs first.
    La MFS se define como el periodo en meses entre la aleatorización y el primer indicio objetivo de progresión radiográfica,determinado por la unidad central de exploración por imágenes, o el fallecimiento durante el estudio (fallecimiento en un plazo de 168 días después de la interrupción definitiva del tratamiento), lo que ocurra en primer lugar.
    E.5.2Secondary end point(s)
    ? Overall survival
    ? Proportion of patients who remain treatment-free 2 years after suspension of study drug treatment at week 37 due to undetectable PSA
    ? Time to castration resistance
    - Supervivencia global;
    - La proporción de pacientes por grupo que siguen sin recibir tratamiento 2 años después de la suspensión del tratamiento con el fármaco investigado en la semana 37 debido a que el PSA es indetectable;
    - El tiempo hasta la resistencia a la castración;
    E.5.2.1Timepoint(s) of evaluation of this end point
    ? Overall survival: the time between randomization and death due to any cause.
    ? Proportion of patients who remain treatment-free 2 years after suspension of study drug treatment at week 37 due to undetectable PSA: no specific timepoint
    ? Time to castration resistance: the time from randomization to the date of the first PSA increase while on study drug treatment that is ? 25% and ? 2 ?g/L (2 ng/mL) above the nadir or screening value, whichever is lower, and that is confirmed by a second consecutive value obtained at least 3 weeks later.
    Supervivencia global: como el periodo en meses entre la aleatorización y el fallecimiento debido a alguna causa.
    - La proporción de pacientes por grupo que siguen sin recibir tratamiento 2 años después de la suspensión del tratamiento con el fármaco investigado en la semana 37 debido a que el PSA es indetectable; no especifica
    - El tiempo hasta la resistencia a la castración; se define como el periodo desde la aleatorización hasta la fecha del primer aumento del PSA durante el transcurso del tratamiento con el fármaco investigado que sea ? 25 % y ? 2 ?g/l (2 ng/ml) superior al
    punto más bajo o al valor durante la selección, el que sea menor, y que se haya confirmado por medio de un segundo valor consecutivo obtenido al menos tres semanas después.
    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 No
    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 Yes
    E.6.13.1Other scope of the trial description
    Quality of life
    Calidad de vida
    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
    La monoterapia con enzalutamida se administrará sin enmascaramiento. El tratamiento con enzalutamida
    Double blind with the exception that enzalutamide monotherapy and leuprolide are open label
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA91
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Brazil
    Canada
    China
    Denmark
    Finland
    France
    Germany
    Italy
    Netherlands
    Spain
    Sweden
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months8
    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: 558
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1302
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1059
    F.4.2.2In the whole clinical trial 1860
    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)
    None
    Ninguno
    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 Decision2015-06-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-05-20
    P. End of Trial
    P.End of Trial StatusOngoing
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