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    Summary
    EudraCT Number:2014-004283-37
    Sponsor's Protocol Code Number:9785-CL-3021
    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:2015-10-22
    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 number2014-004283-37
    A.3Full title of the trial
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study
    to Assess the Efficacy and Safety of Enzalutamide in Subjects
    with Advanced Hepatocellular Carcinoma
    Estudio de fase 2, aleatorizado, doble ciego y controlado con placebo para evaluar la eficacia y la seguridad de enzalutamida en sujetos con carcinoma hepatocelular avanzado
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the safety and effectiveness of enzalutamide in patients with advanced hepatocellular carcinoma
    Un estudio para evaluar la seguridad y efectividad de enzalutamida en pacientes con carcinoma hepatocelular avanzado
    A.4.1Sponsor's protocol code number9785-CL-3021
    A.5.4Other Identifiers
    Name:INDNumber:127011
    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 SponsorAstellas Pharma Global Development, 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 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 organisationAstellas Pharma Europe B.V.
    B.5.2Functional name of contact pointService Desk - Global Clinical Dev.
    B.5.3 Address:
    B.5.3.1Street AddressSylviusweg 62
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 BE
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31715455050
    B.5.5Fax number+31715455501
    B.5.6E-mailcontact@nl.astellas.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name 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.3.4Pharmaceutical 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.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
    Male and female subjects with HCC of any etiology who have progressed on or were intolerant to sorafenib or other anti-VEGF therapy in the advanced setting
    Hombres y mujeres con CHC avanzado de cualquier etiología que hayan progresado o no hayan tolerado sorafenib u otro tratamiento con factor del crecimiento endotelial antivascular (VEGF) en un contexto avanzado
    E.1.1.1Medical condition in easily understood language
    Male and female subjects with Advanced Hepatocellular Carcinoma
    Hombres y mujeres con carcinoma hepatocelular avanzado
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10073071
    E.1.2Term Hepatocellular carcinoma
    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 the efficacy of enzalutamide in subjects with advanced hepatocellular carcinoma (HCC) as measured by overall survival (OS).
    Evaluar la eficacia de enzalutamida en sujetos con carcinoma hepatocelular (CHC) avanzado determinada por la supervivencia global (SG)
    E.2.2Secondary objectives of the trial
    To evaluate:
    - the safety of enzalutamide in subjects with advanced HCC.
    - the pharmacokinetics (PK) of enzalutamide and the active metabolite N-desmethyl enzalutamide in subjects with advanced HCC.
    - the Time to Progression (TTP) and Progression Free Survival (PFS) of enzalutamide as compared to placebo in subjects with advanced HCC.
    Evaluar:
    - la seguridad de enzalutamida en sujetos con CHC avanzado.
    - la farmacocinética (FC) de enzalutamida y el metabolito activo N-desmetil enzalutamida en sujetos con CHC avanzado.
    - el tiempo hasta la progresión (THP) y la supervivencia sin progresión (SSP) de enzalutamida en comparación con placebo en sujetos con CHC avanzado.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Waivers to the inclusion and exclusion criteria will NOT be allowed.
    1. Subject has consented and signed an Institutional Review Board (IRB)/Independent Ethics
    Committee (IEC) approved written Informed Consent and privacy language as per national
    regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] for U.S. sites)
    prior to any study-related procedures (including withdrawal of prohibited medication, if
    applicable).
    2. Subject is ? 18 years of age.
    3. Subject has histological diagnosis of advanced HCC of any etiology. Clinical diagnosis by the
    European Association for the Study of the Liver (EASL) criteria is acceptable. For subjects
    without cirrhosis, histological confirmation is required (archive samples are acceptable).
    4. Subject has BCLC stage B or C.
    5. Subject?s lesions are not amenable to local therapies which may be beneficial, such as
    transarterial chemoembolization (TACE), radiofrequency ablation, etc., and the subject is not a
    candidate for any curative treatments such as resection or liver transplant.
    6. Subject has hepatic function status of Child Pugh Class A at Screening.
    7. Subject received prior systemic treatment for HCC with sorafenib or other anti-VEGF therapy
    and had confirmed disease progression or discontinued treatment due to a drug-related toxicity.
    Subject may have received 1 line of systemic investigational therapy after sorafenib/anti-VEGF
    treatment.
    8. Subject has adequately recovered from toxicities due to prior HCC therapy to ? grade 1.
    9. Subject has an ECOG performance status ? 1 at Screening and on Day 1.
    10. Subject has available formalin-fixed, paraffin-embedded tumor specimen that enabled the
    diagnosis of HCC with adequate viable tumor cells in a tissue block (preferred) or ? 10
    (20 preferred) unstained serial slides accompanied by an associated pathology report is required
    prior to enrollment. Archival or fresh biopsy tissue is acceptable.
    11. Subject has an estimated life expectancy of at least 3 months on Day 1, in the opinion of the
    investigator
    12. Female subject is either:
    ? Not of childbearing potential:
    -postmenopausal (defined as no spontaneous menses for at least 12 consecutive months prior to Screening with follicle-stimulating hormone [FSH] > 40 IU/L for women < 55 years of age at Screening), or
    -documented to be surgically sterile or status posthysterectomy (at least 1 month prior to
    Screening).
    ? Or, if of childbearing potential:
    - must have a negative urine pregnancy test at Screening and on Day 1 before the first dose of study drug is administered, and
    - must use 2 acceptable methods of birth control* from Screening through 3 months after the last dose of study drug.
    13. Male subject and his female partner who is of childbearing potential must use 2 acceptable
    methods of birth control from Screening through 3 months after the last dose of study drug.
    *Two acceptable methods of birth control are as follows:
    ? Condom (barrier method of contraception);
    AND
    ? One of the following is required:
    - Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female subject or female partner of a male subject;
    - Additional barrier method: contraceptive sponge or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female subject or female partner of a male subject.
    - For male subject or male partner of female subject, vasectomy or other procedure resulting in infertility (e.g., bilateral orchiectomy) performed at least 6 months before Screening.
    -Tubal ligation in the female partner of a male subject performed at least 6 months before Screening.
    - Established and ongoing use of oral, injected, or implanted hormonal contraceptive by female partner of a male subject.
    14. Female subject must not be breastfeeding at Screening or during the study period and for 3
    months after final study drug administration.
    15. Subject must agree not to donate sperm or ova from first dose of study drug through 3 months
    after the last dose of study drug.
    16. Throughout the study, male subject must use a condom if having sex with a pregnant woman.
    17. Subject must be able to swallow study drug and comply with study requirements.
    18. Subject agrees not to participate in another interventional study while on treatment.
    NO se permitirán las exenciones de los criterios de inclusión o exclusión.
    1. El sujeto ha aceptado y firmado el consentimiento informado por escrito aprobado por el Comité de ética de la investigación clínica (CEIC) y la declaración de privacidad según las normativas nacionales (p.ej., Ley de portabilidad y responsabilidad de los seguros médicos [HIPAA] para centros de los EE. UU.) antes de cualquier procedimiento relacionado con el estudio (incluida la retirada de la medicación prohibida, si procede).
    2. El sujeto tiene ?18 años de edad.
    3. El sujeto tiene un diagnóstico histológico de CHC avanzado de cualquier etiología. Se acepta el diagnóstico clínico de la Asociación Europea para el estudio del hígado (EASL). En los sujetos sin cirrosis, se requiere la confirmación histológica (se aceptan muestras archivadas).
    4. El sujeto está en estadio B o C de BCLC.
    5. Las lesiones del sujeto no son susceptibles de tratamiento local que pueda ser beneficioso, como quimioembolización transarterial (TACE), ablación por radiofrecuencia, etc., y el sujeto no es candidato a ningún tratamiento curativo, como resección o trasplante de hígado.
    6. El sujeto presenta un estado funcional del hígado de clase A de Child Pugh en la selección.
    7. El sujeto recibió tratamiento sistémico previo para el CHC con sorafenib u otro tratamiento anti-VEGF y presentó una progresión de la enfermedad confirmada o abandono del tratamiento por toxicidad relacionada con el fármaco. El sujeto podrá haber recibido una línea de tratamiento sistémico en fase de investigación tras el tratamiento con sorafenib/anti-VEGF.
    8. El sujeto se ha recuperado adecuadamente hasta un grado ?1 de toxicidades debidas al tratamiento previo para el CHC
    9. El sujeto presenta un estado funcional de ECOG ?1 en la selección y el día 1.
    10. El sujeto dispone de muestras del tumor fijadas en formalina e incluidas en parafina que permitieron el diagnóstico de CHC con células tumorales viables adecuadas en un bloque de tejido (preferiblemente) o ? 10 (20 preferiblemente) láminas en serie no teñidas junto con un informe de anatomía patológica antes de la inclusión. Se acepta el tejido de biopsia de archivo o fresco.
    11. El sujeto tiene una esperanza de vida prevista de al menos 3 meses el día 1, en opinión del investigador.
    12. En el caso de sujetos de sexo femenino:
    ? No es fértil: posmenopáusica (definida como menstruación no espontánea durante al menos 12 meses seguidos antes de la selección con niveles de folitropina [FSH] > 40 UI/l en mujeres < 55 años de edad en la selección),o con esterilización quirúrgica documentada o en situación de poshisterectomía (al menos 1 mes antes de la selección).
    ? O, si es fértil: debe presentar una prueba de embarazo en orina negativa en la selección y el día 1 antes de la administración de la primera dosis del fármaco del estudio, y debe usar dos métodos anticonceptivos aceptables* desde la selección hasta 3 meses después de la última dosis del fármaco del estudio.
    13. El sujeto de sexo masculino y su pareja femenina fértil deben usar 2 métodos anticonceptivos aceptables desde la selección hasta 3 meses después de la última dosis del fármaco del estudio.
    *Dos métodos anticonceptivos aceptables son:
    ? Preservativo (método anticonceptivo de barrera);
    Y
    ? Se requiere uno de los siguientes:
    ? Colocación de un dispositivo intrauterino (DIU) o un sistema intrauterino (SIU) por la participante o pareja femenina de un sujeto masculino;
    ? Método de barrera adicional: esponja anticonceptiva o capuchón oclusivo (diafragma o capuchones cervicales / de bóveda) con espuma/gel/película/ crema/supositorio anticonceptivo por parte de la participante o la pareja femenina de un sujeto de sexo masculino.
    ? En los sujetos masculinos o las parejas masculinas de participantes femeninas, la vasectomía u otros procedimiento que produzca infertilidad (p. ej., orquiectomía bilateral) realizados al menos 6 meses antes de la selección.
    ? Ligadura de trompas en pareja femenina de un sujeto de sexo masculino realizada al menos 6 meses antes de la selección.
    ? Uso establecido y continuado de anticonceptivos hormonales orales, inyectables o implantados por parte de la pareja femenina de un sujeto de sexo masculino.
    14. La participante femenina no debe estar amamantando en la selección ni durante el período de estudio y hasta 3 meses después de la administración final del fármaco del estudio.
    15. El sujeto debe aceptar no donar esperma ni óvulos desde la primera dosis del fármaco del estudio y hasta 3 meses después de la última dosis del fármaco del estudio.
    16. Durante todo el estudio, el sujeto de sexo masculino debe utilizar un preservativo si mantiene relaciones sexuales con una mujer embarazada.
    17. El sujeto debe poder ser capaz de tragar el fármaco del estudio y cumplir los requisitos del estudio.
    18. El sujeto acepta no participar en otro estudio de intervención durante el tratamiento.
    E.4Principal exclusion criteria
    1. Subject has a severe concurrent disease, infection or comorbidity that, in the judgment of the
    investigator, would make the subject inappropriate for enrollment.
    2. Subject has fibrolamellar variant of HCC.
    3. Subject has status of Child-Pugh Class B or C at Screening.
    4. Subject has a history of organ allograft including liver transplant.
    5. Subject has uncontrolled symptomatic ascites.
    6. Subject has known or suspected brain metastasis or active leptomeningeal disease.
    7. Subject has a history of a non-HCC malignancy with the following exceptions:
    -The subject with a previous history of a noninvasive carcinoma is eligible if in the opinion of
    the investigator he/she has had successful curative treatment any time prior to Screening and
    requires no further therapy for the malignancy.
    -For all other malignancies, the subject is eligible if he/she has undergone potentially curative
    therapy and has been considered disease free for at least 3 years prior to Screening.
    8. Subject has inadequate marrow, hepatic, and/or renal function at the Screening Visit defined as:
    -Absolute neutrophil count < 1.5 x109/L (< 1500 cells/mm3)
    -Platelet count < 50 x109/L (< 50,000 cells/mm3)
    -Hemoglobin < 8.5 g/dL (< 5.3 mmol/L)
    -International normalized ratio > 1.7
    -Albumin < 2.8 g/dL (< 28 g/L)
    -Total bilirubin > 2 x ULN
    -AST or ALT > 5 x ULN
    -Creatinine > 1.5 x ULN
    9. Subject has a history of seizure or any condition that may predispose to seizure (e.g., prior
    cortical stroke, significant brain trauma, encephalopathy within 3 months of Day 1).
    10. Subject has a history of esophageal varices within 3 months before the Day 1 visit.
    11. Subject has a history of loss of consciousness or transient ischemic attack within 12 months
    before the Day 1 visit.
    12. Subject has clinically significant cardiovascular disease including:
    -Myocardial infarction within 6 months before the Day 1 visit.
    -Uncontrolled angina within 6 months before the Day 1 visit.
    -Congestive heart failure New York Heart Association (NYHA) Class III or IV or history of
    congestive heart failure NYHA Class III or IV in the past, unless a Screening echocardiogram
    or multi-gated acquisition scan performed within 3 months before the Day 1 visit reveals a
    left ventricular ejection fraction that is ? 45%.
    - History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, Torsade 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 mmHg on 2 consecutive measurements at the Screening visit.
    -Bradycardia (in the presence of known cardiovascular disease) as indicated by a heart rate of
    < 50 beats per minute on the Screening electrocardiogram (ECG) recording.
    -Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg on 2 consecutive measurements at the Screening visit.
    13. Subject has a gastrointestinal disorder affecting absorption.
    14. Subject had previous local therapy (e.g., surgery, radiation therapy, hepatic arterial therapy,
    chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation)
    within 14 days prior to Day 1, has not recovered from toxicities from prior local therapy or may
    require major surgical procedure during the course of the study.
    15. Subject has received chemotherapy, immunotherapy or any other systemic anticancer therapy
    (including sorafenib) or any other investigational drug within 14 days prior to the Day 1 visit.
    16. Subject has received an agent that either blocks androgen synthesis or targets the AR (e.g.,
    abiraterone acetate, bicalutamide, enzalutamide, ARN-509 or other investigational AR signaling
    inhibitors).
    17. Subject has used any of the following within 28 days before the Day 1visit:
    -5-? reductase inhibitors
    - Systemic androgens and estrogens (vaginal estrogen creams are allowed)
    -Herbal therapies, with an antitumor effect.
    18. Subject has a known history of positive test for Human Immunodeficiency Virus.
    19. Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or any of
    the enzalutamide capsule components, including caprylocaproyl polyoxylglycerides (Labrasol),
    butylated hydroxyanisole and butylated hydroxytoluene.
    20. Subject has addictive/substance abuse problems.
    21. Subject has any other condition or reason that, in the opinion of the investigator, interferes with
    the ability of the subject to participate in the trial, places the subject at undue risk or complicates
    the interpretation of safety data.
    1.El sujeto sufre una enfermedad concurrente grave,una infección o comorbilidad que, en opinión del investigador,haría que el sujeto no fuera adecuado para su inclusión.2.Padece una variante fibrolamelar de CHC.3.El sujeto presenta un estado de clase B o C de Child-Pugh en la selección.4.Tiene antecedentes de aloinjerto de órgano incluido el trasplante hepático.5.Sufre una ascitis sintomática no controlada.6.El sujeto tiene metástasis cerebral conocida o presunta o enfermedad leptomeníngea activa. 7.Tiene antecedentes de neoplasia maligna distinta del CHC con las siguientes excepciones:?El sujeto con antecedentes de carcinoma no invasivo es elegible si,en opinión del investigador,había recibido un tratamiento curativo con éxito en cualquier momento antes dela selección y no requiere más tratamiento para la neoplasia maligna.?Para todas las restantes neoplasias malignas,el sujeto es elegible si se ha sometido a un tratamiento potencialmente curativo y se ha considerado libre de la enfermedad durante al menos 3 años antes de la selección.8.Tiene una función medular,hepática o renal insuficiente en la visita de selección,definida como:?Cifra absoluta de neutrófilos <1,5x109/l (<1500 células/mm3)?Recuento plaquetario <50x109/l (<50 000 células/mm3)?Hemoglobina<8,5 g/dl (<5,3 mmol/l)?Cociente internacional normalizado (CIN)>1,7?Albúmina<2,8 g/dl (<28 g/l)?Bilirrubina total>2xLSN?ASAT o ALAT>5xLSN?Creatinina >1,5x LSN.9.Tiene antecedentes de convulsiones o cualquier trastorno que pueda predisponer a convulsiones (p.ej.,ictus cortical previo,traumatismo cerebral significativo,encefalopatía,en los 3 meses siguientes al día 1).10.Tiene antecedentes de varices esofágicas en los 3 meses anteriores a la visita del día 1.
    11.Tiene antecedentes de pérdida de conocimiento o accidente isquémico transitorio en los 12 meses anteriores a la visita del día 1.
    12.Tiene una enfermedad cardiovascular clínicamente significativa que incluye:?Infarto de miocardio en los 6 meses anteriores a la visita del día 1.?Angina de pecho no controlada en los 6 meses anteriores a la visita del día 1.? Insuficiencia cardíaca congestiva de Clase III o IV de la Asociación de Cardiología de Nueva York (New York Heart Association (NYHA)) en la actualidad o en el pasado,salvo que un ecocardiograma o una ventriculografía isotópica en la selección realizados en los 3 meses previos a la visita del día 1 revelasen una fracción de eyección ventricular de?45 %.? Antecedentes de arritmias ventriculares clínicamente significativas (p.ej. taquicardia ventricular,fibrilación ventricular, taquicardia ventricular en entorchado [torsade de pointes]).?Antecedentes de bloqueo cardíaco de segundo o tercer grado de Mobitz II sin colocación de marcapasos permanente.?Hipotensión indicada mediante presión arterial sistólica <86 mmHg en dos determinaciones consecutivas en la visita de selección.?Bradicardia (en presencia de enfermedad cardiovascular conocida) indicada por una frecuencia cardíaca de <50 latidos por minuto en el registro del electrocardiograma (ECG) en la selección.? Hipertensión no controlada indicada mediante presión arterial sistólica >170 mmHg o presión arterial diastólica >105 mmHg en 2 determinaciones consecutivas en la visita de selección.13.Sufre un trastorno digestivo que afecta a la absorción.14.Recibió un tratamiento local previo (p.ej., cirugía, radioterapia, terapia arterial hepática,quimioembolización,ablación por radiofrecuencia,inyección percutánea de etanol o crioablación) en los 14 días previos al día 1,no se ha recuperado de las toxicidades del tratamiento local previo o puede requerir una intervención quirúrgica mayor durante el transcurso del estudio.15.Ha recibido quimioterapia,inmunoterapia u otra terapia antineoplásica sistémica (incluido sorafenib) o cualquier fármaco en fase de investigación en los 14 días previos a la visita del día1.
    16.Ha recibido un fármaco que o bien bloquea la síntesis de andrógenos o se dirige al RA(p.ej., acetato de abiraterona, bicalutamida, enzalutamida,ARN-509 u otros moduladores de la señalización del RA en fase de investigación).17.Ha usado cualquiera de los siguientes en los 28 días previos a la visita del día 1:?Inhibidores de la 5-? reductasa?Andrógenos y estrógenos sistémicos (se permiten los estrógenos vaginales en crema)?Hierbas medicinales, con efecto antineoplásico.18.Tiene antecedentes conocidos de resultado positivo para el virus de la inmunodeficiencia humana.19.El sujeto ha mostrado una reacción de hipersensibilidad al principio activo o a cualquiera de los componentes de la cápsula de enzalutamida,como caprilocaproil polioxilglicéridos (Labrasol),hidroxianisol butilado e hidroxitolueno butilado.20.El sujeto tiene problemas adictivos/de abuso de sustancias.21.Tiene cualquier otro trastorno o motivo por el cual, en opinión del investigador,interfiere con su capacidad para participar en el ensayo,sitúa al sujeto en un riesgo indebido o complica la interpretación de los datos de seguridad.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable is overall survival (OS).
    La variable principal de eficacia es la supervivencia global
    E.5.1.1Timepoint(s) of evaluation of this end point
    OS is defined as the time from the date of randomization until date of death from any cause
    La supervivencia global se define como el tiempo desde la fecha de la aleatorización hasta la fecha de la muerte por cualquier causa.
    E.5.2Secondary end point(s)
    Safety Endpoints:
    The safety of enzalutamide will be assessed on an ongoing basis by evaluation of AEs/serious adverse
    events, clinical safety laboratory tests, vital signs, and other safety measures.
    Pharmacokinetic Endpoints:
    Predose plasma concentrations of enzalutamide and N-desmethyl enzalutamide will be analyzed.
    Efficacy Endpoints:
    ? Time to Progression (TTP),
    ? Progression Free Survival (PFS)
    Criterios de valoración de la seguridad:
    Se evaluará la seguridad de enzalutamida de manera continuada mediante la evaluación de los AA/acontecimientos adversos graves, las pruebas clínicas de laboratorio para la seguridad, constantes vitales y otras medidas de la seguridad.
    Criterios de valoración farmacocinéticos:
    Se analizarán las concentraciones plasmáticas de enzalutamida y N-desmetil enzalutamida previas a la administración de la dosis.
    Criterios de valoración de la eficacia:
    ? El tiempo hasta la progresión (THP),
    ? La Supervivencia sin progresión (SSP)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy Endpoints:
    ? TTP, defined as the time from the date of randomization until the date of the first
    radiographically documented disease progression as assessed by the investigator.
    ? PFS, defined as the time from the date of randomization until the date of documented
    radiographic disease progression according to Response Evaluation Criteria in Solid Tumors
    (RECIST) 1.1 or death from any cause on study, whichever occurs first as assessed by the
    investigator.
    Criterios de valoración de la eficacia:
    ? El THP, definido como el tiempo desde la aleatorización hasta la fecha de la primera progresión radiográficamente documentada de la enfermedad, según la evaluación del investigador.
    ? La SSP, definida como el tiempo desde la fecha de la aleatorización hasta la fecha de la progresión radiográfica de la enfermedad según los criterios de evaluación de la respuesta en tumores sólidos (RECIST) 1.1 o la muerte por cualquier causa durante el estudio, lo que suceda primero según la evaluación del investigador.
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned20
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Canada
    France
    Hong Kong
    Italy
    Korea, Republic of
    Puerto Rico
    Singapore
    Spain
    Taiwan
    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 sujeto
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    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: 72
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 72
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 54
    F.4.2.2In the whole clinical trial 144
    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)
    Plans for treatment or care after for the subject is per the treating physician's discretion and what is best for the subject.
    Las previsiones de tratamiento o cuidados médicos para los pacientes están sujetos a la opinión del médico que les trata y lo que es mejor para dicho paciente.
    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 Decision2015-12-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-23
    P. End of Trial
    P.End of Trial StatusOngoing
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