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    EudraCT Number:2012-004322-24
    Sponsor's Protocol Code Number:ARN-509-003
    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:2013-08-08
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2012-004322-24
    A.3Full title of the trial
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Study of ARN-509 in Men with Non-Metastatic (M0) Castration-Resistant Prostate Cancer
    Estudio de fase III, multicéntrico, aleatorizado, doble ciego, de ARN-509 controlado con placebo en hombres con cáncer de próstata no metastásico (M0) y resistente a la castración
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical study to assess the safety and effectiveness of ARN-509 in men with Castration-Resistant Prostate Cancer (prostate cancer not responsive to castration treatment)
    Ensayo clínico que analiza la eficacia y la seguridad de ARN-509 en hombres con con cáncer de próstata y resistente a la castración (cancer de prostata que no responde al tratamiento de castración)
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberARN-509-003
    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 SponsorAragon Pharmaceuticals, 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 supportAragon Pharmaceuticals Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAragon Pharmaceuticals, Inc
    B.5.2Functional name of contact pointVP, Clinical Development
    B.5.3 Address:
    B.5.3.1Street Address12780 El Camino Real, Suite 301
    B.5.3.2Town/ citySan Diego
    B.5.3.3Post codeCA 92130
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1858369 7627
    B.5.5Fax number+1858639 7662
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code ARN-509
    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 INNARN-509
    D.3.9.1CAS number 956104-40-8
    D.3.9.2Current sponsor codeARN-509
    D.3.9.3Other descriptive nameARN-509
    D.3.9.4EV Substance CodeSUB96228
    D.3.10 Strength
    D.3.10.1Concentration unit % (W/W) percent weight/weight
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Castration-Resistant Prostate Cancer
    Cáncer de próstata resistente a la castración
    E.1.1.1Medical condition in easily understood language
    Prostate cancer with rapidly rising PSA not responsive to hormonal treatment.
    Cáncer de próstata con un rápido aumento de los niveles de PSA y que no responde al tratamiento hormonal.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level PT
    E.1.2Classification code 10036909
    E.1.2Term Prostate cancer metastatic
    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 demonstrate superiority in the metastasis-free survival (MFS) of men with high risk NM-CRPC treated with ARN-509 versus placebo
    Demostrar que la supervivencia sin metástasis (MFS) en hombres con CPRC de alto riesgo sin metástasis tratados con ARN-509 es superior, en comparación con el grupo de placebo
    E.2.2Secondary objectives of the trial
    To compare the overall survival (OS) of men with high risk NM-CRPC treated with ARN-509 versus placebo and:
    -To compare the time to symptomatic progression in men with high risk NM-CRPC treated with ARN-509 versus placebo
    -To compare the time to initiation of cytotoxic chemotherapy in men with high risk NM-CRPC treated with ARN-509 versus placebo
    -To compare the radiographic progression-free survival (PFS) of men with high risk NM-CRPC treated with ARN-509 versus placebo
    -To compare the time to metastasis (TTM) in men with high risk NM-CRPC treated with ARN-509 versus placebo
    -To compare patient reported outcomes (PROs) of health-related quality of life and prostate cancer-specific symptoms in men with high risk NM-CRPC treated with ARN-509 versus placebo
    -To evaluate the safety and tolerability of ARN-509
    -To evaluate the population pharmacokinetics of ARN-509
    -To evaluate the effect of ARN-509 on ventricular repolarization in a subset of patients from selected clinical sites
    Comparar la supervivencia global (SG) en hombres con CPRC de alto riesgo sin metástasis tratados con ARN-509, en comparación con el placebo.

    Comparar en hombres con CPRC de alto riesgo sin metástasis tratados con ARN-509, en comparación con el placebo:
    - el tiempo que transcurre hasta la progresión sintomática
    - el tiempo transcurrido hasta el inicio de la quimioterapia citotóxica
    - la supervivencia libre de progresión (SLP) con medios radiológicos
    - el tiempo que transcurre hasta la presencia de metástasis (TTM)
    - los resultados percibidos por el paciente (RPP) de la calidad de vida relacionada con la salud y los síntomas específicos del cáncer de próstata

    Evaluar la seguridad y la tolerabilidad de ARN-509.

    Evaluar la farmacocinética poblacional de ARN-509.

    Evaluar el efecto de ARN-509 sobre la repolarización ventricular en un subgrupo de pacientes en determinados centros clínicos.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    VENTRICULAR REPOLARIZATION SUB-STUDY: (Appendix 8, Protocol Version 3.0 08 May 2013)
    To evaluate the effect of ARN-509 on ventricular repolarization in a subset of patients from selected clinical sites. The effect of ARN-509 on ventricular repolarization will be centrally analyzed by a third-party cardiac safety laboratory in a subset of 100 patients enrolled at selected sites that will be participating in the main protocol. Both ARN-509 and placebo patients will be enrolled in a blinded manner as per the main protocol randomization criteria.
    -The primary objective of this sub-study is to evaluate whether ARN-509 has a threshold pharmacological effect on cardiac repolarization, as detected by changes in electrocardiogram (ECG) QT intervals corrected for heart rate by Fridericia's correction method (QTcF)
    -The secondary objectives of this study sub-study are as follows:
    -To investigate the effect of ARN-509 on the following ECG parameters: PR, RR, QRS, QT, QTcB (Bazett's correction method), and T-Wave morphology
    -To further characterize the pharmacokinetic (PK) profile of ARN-509 and to assess the exposure-effect relationships (if any) between ARN-509 plasma concentrations and ECG interval change
    ESTUDIO SECUNDARIO SOBRE LA REPOLARIZACIÓN VENTRICULAR (Apendice 8, Protocolo Versión 3.0 de fecha 08 de Mayo de 2013).

    Evaluar el efecto de ARN-509 sobre la repolarización ventricular en un subgrupo de pacientes de determinados centros. El efecto de ARN-509 sobre la repolarización ventricular se analizará en un laboratorio de seguridad cardiaca externo central en un subgrupo de 100 pacientes incorporados en centros seleccionados que formarán parte del protocolo principal. Los pacientes de ARN-509 y de placebo desconocerán la asignación real del tratamiento de acuerdo con los criterios de aleatorización del protocolo principal.
    - El objetivo principal de este estudio secundario consiste en evaluar si ARN-509 tiene un efecto farmacológico liminar sobre la repolarización cardiaca, tal y como se ha detectado en las variaciones de los intervalos QT del electrocardiograma (ECG) corregido para la frecuencia cardiaca con la técnica de corrección de Fridericia (QTcF). . - Los objetivos secundarios de este estudio secundario del estudio son los siguientes:
    - Investigar el efecto de ARN-509 en los siguientes parámetros del ECG: PR, RR, QRS, QT, QTcB (técnica de corrección de Bazett) y morfología de la onda T.
    - Mejorar aún más la caracterización de las características farmacocinéticas (FC) de ARN-509 y evaluar las relaciones del efecto de exposición (si existen) entre las concentraciones plasmáticas de ARN-509 y la variación del intervalo de ECG
    E.3Principal inclusion criteria
    1. Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features, with high risk for development of metastases, defined as PSADT ? 10 months randomization and throughout the study
    4. Patients currently receiving bone loss prevention treatment with bone-sparing agents (e.g., bisphosphonates, denosumab [Prolia®]) must be on stable doses for at least 4 weeks prior to randomization
    5. Patients who received a first generation anti-androgen (e.g., bicalutamide, flutamide, nilutamide) as part of an initial combined androgen blockade therapy or as second-line hormonal therapy must show continuing disease (PSA) progression off the anti-androgen for at least 4 weeks prior to randomization
    6. At least 4 weeks must have elapsed from the use of 5-? reductase inhibitors (e.g., dutasteride, finasteride, aminoglutethamide), estrogens, and any other anti-cancer therapy prior to randomization, including chemotherapy given in the adjuvant/neoadjuvant setting (e.g., clinical trial)
    7. At least 4 weeks must have elapsed from major surgery or radiation therapy prior to randomization
    8. Age ? 18 years
    9. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
    10. Resolution of all acute toxic effects of prior therapy or surgical procedure to Grade ? 1 or baseline prior to randomization
    Adequate organ function as defined by the following criteria:
    -Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ? 2.5 x upper limit of normal (ULN)
    -Total serum bilirubin ? 1.5 x ULN
    - Serum creatinine ? 2 x ULN
    - Absolute neutrophil count (ANC) ? 1500/?L
    - Platelets ? 100,000/?L
    - Hemoglobin ? 9.0 g/dL
    o Administration of growth factors or blood transfusions will not be allowed within 4 weeks of the hematology labs required to confirm eligibility
    12. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to randomization
    13. Willingness and ability to comply with scheduled visits, treatment plans, laboratory and radiographic assessments, and other study procedures, including ability to swallow large capsules, the completion of patient reported outcomes questionnaires and long-term follow-up visits
    1.Adenocarcinoma de próstata con diagnóstico histológico o citológico sin diferenciación neuroendocrina o características microcíticas, con alto riesgo de evolución metastásica, que se distingue por un tiempo de duplicación del PSA =<10 meses 2.Cáncer de próstata resistente a la castración que se manifiesta durante la terapia de privación androgénica continua (TPA)/posorquiectomía, que se identifica con 3 aumentos consecutivos del PSA, apartado 1 semana como mínimo, lo que provoca dos aumentos del 50 % sobre el nadir, con el último PSA >2 ng/ml 3.Mantenimiento de los niveles de testosterona indicativos de castración (<50 ng/dl [1,72 nmol/l]) durante las 4 semanas anteriores a la aleatorización y en todo el estudio 4.Los pacientes que actualmente reciben tratamiento de prevención contra la osteoporosis con inhibidores de la resolución ósea (por ejemplo, bisfosfonatos, denosumab [Prolia®]) deben hacerlo en dosis estables durante al menos 4 semanas antes de la aleatorización 5.Los pacientes a los que se les administra un antiandrógeno de primera generación (por ejemplo, bicalutamida, flutamida, nilutamida) como parte de una terapia inicial combinada de bloqueo de andrógenos o como un tratamiento hormonal de segunda línea deben mostrar una progresión continua de la enfermedad (PSA) sin antiandrógenos durante al menos 4 semanas antes de la aleatorización 6.Deben haber transcurrido 4 semanas como mínimo desde la administración de los inhibidores de la 5-?-reductasa (por ejemplo, dutasterida, finasterida, aminoglutetimida), estrógenos y cualquier otro tratamiento antineoplásico antes de la aleatorización, entre los que se incluyen la quimioterapia adyuvante/neoadyuvante (por ejemplo, ensayo clínico) 7.Deben haber transcurrido 4 semanas como mínimo desde la cirugía mayor o la radioterapia antes de la aleatorización 8.Edad >=18 años 9.Estado funcional 0 o 1 del ECOG (Eastern Cooperative Oncology Group) 10.Remisión de todos los efectos tóxicos agudos del tratamiento anterior o del procedimiento quirúrgico al nivel 1 o a los datos iniciales antes de la aleatorización 11.Estado orgánico adecuado según se define por los criterios siguientes: - Aspartato-aminotransferasa (ASAT) y alanina-aminotransferasa (ALAT) en suero <=2,5 x el límite superior de la normalidad (LSN) - Bilirrubina total en suero <=1,5 x LSN - Creatinina sérica <=2 x LSN - Recuento absoluto de neutrófilos (RAN) 1500/?L- Trombocitos ? 100,000/?L - Hemoglobina >= 9,0 g/dl La administración de factores de crecimiento o transfusiones sanguíneas no se permitirán en las 4 semanas anteriores a la realización de los análisis de sangre necesarios para confirmar la idoneidad de los pacientes 12.Documento de consentimiento informado con fecha y firma en el que se indica que el paciente (o el representante legal autorizado) ha recibido toda la información pertinente sobre el ensayo antes de la aleatorización 13.Disposición y aptitud para cumplir con el calendario de visitas, los planes de tratamiento, análisis de laboratorio o evaluaciones radiológicas y otros procedimientos del estudio, entre los que se incluye la capacidad para tragar cápsulas grandes, rellenado de los cuestionarios de los resultados percibidos por el paciente y visitas de seguimiento a largo plazo
    E.4Principal exclusion criteria
    1.Presence of distant metastases, confirmed by blinded independent central review (BICR), including CNS and vertebral or meningeal involvement. Exception: pelvic lymph nodes < 2 cm in short axis (N1) located below the iliac bifurcation are allowed
    2. Symptomatic loco-regional disease requiring medical intervention, such as moderate or severe urinary obstruction or hydronephrosis due to primary tumor (e.g., tumor obstruction of bladder trigone)
    3. Prior treatment with second generation anti-androgens (e.g., enzalutamide)
    4. Prior treatment with CYP17 inhibitors (e.g., abiraterone, orteronel, galeterone, ketoconazole)
    5. Prior treatment with radiopharmaceutical agents (e.g., Strontium-89), immunotherapy (e.g., sipuleucel-T), or any other investigational agent for NM-CRPC
    6. Prior chemotherapy for prostate cancer except if administered in the adjuvant/neoadjuvant setting
    7. History of seizure or condition that may pre-dispose to seizure (e.g., stroke within 1 year prior to randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign CNS or meningeal disease which may require treatment with surgery or radiation therapy)
    8. Concurrent therapy with any of the following (all must have been discontinued or substituted for at least 4 weeks prior to randomization):
    -Medications known to lower the seizure threshold
    -Herbal and non-herbal products that may decrease PSA levels (i.e., saw palmetto, pomegranate juice)
    -Systemic (oral/IV/IM) corticosteroids. Short term use (? 4 weeks) of corticosteroids during the study is allowed if clinically indicated, but it should be tapered off as soon as possible
    -Any other experimental treatment on another clinical trial
    9. History or evidence of any of the following conditions:
    -Any prior malignancy (other than adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) within 5 years prior to randomization
    -Severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to randomization
    -Uncontrolled hypertension (? 160 mmHg systolic blood pressure and/or diastolic blood pressure ? 100 mmHg)
    -Gastrointestinal disorder affecting absorption
    -Active infection, such as human immunodeficiency virus (HIV)
    -Any other condition that, in the opinion of the Investigator, would impair the patient?s ability to comply with study procedures
    1.Presencia de metástasis a distancia, confirmada por un comité central de revisión independiente que ignora la asignación del tratamiento (blinded independent central review, BICR), incluido el SNC y la afectación vertebral o meníngea. Excepción: se permiten ganglios linfáticos pélvicos <2 cm en el eje corto (N1) situados debajo de la bifurcación ilíaca
    2.Patología locorregional sintomática que precisa intervención médica, como, por ejemplo, obstrucción urinaria moderada o grave, o bien hidronefrosis a causa de un tumor primario (por ejemplo, obstrucción tumoral del trígono vesical)
    3.Tratamiento previo con antiandrógenos de segunda generación (por ejemplo, enzalutamida)
    4.Tratamiento previo con inhibidores CYP17 (por ejemplo, abiraterona, orteronel, galeterone, ketoconazol)
    5.Tratamiento previo con radiofármacos (por ejemplo, Estroncio-89), inmunoterapia (por ejemplo, sipuleucel-T) o cualquier otro producto en investigación para tratar el CPRC sin metástasis (por ejemplo, denosumab [Xgeva®])
    6.Quimioterapia previa para el cáncer de próstata, a excepción de si es adyuvante/neoadyuvante
    7.Antecedentes de convulsiones o predisposición a sufrir convulsiones (por ejemplo, accidente cerebrovascular durante el año anterior a la aleatorización, anomalía arteriovenosa cerebral, schwannoma, meningioma u otras patologías del SNC o meníngeas benignas que pueden precisar un tratamiento con intervención quirúrgica o radiación)
    8.Tratamiento concomitante con alguno de los siguientes medicamentos (todos deben haberse interrumpido o sustituido al menos 4 semanas antes de la aleatorización):
    -Medicamentos que se sabe disminuyen el umbral de convulsión
    -Productos fitoterapéuticos y de otro tipo que pueden disminuir los niveles de PSA (es decir, palma enana americana, zumo de granada)
    -Corticoesteroides sistémicos (oral/i.v./intramuscular) Se permite la administración breve (?4 semanas) de corticoesteroides durante el estudio si está clínicamente recomendado, pero su administración debe disminuirse de manera progresiva lo antes posible
    -Cualquier otro tratamiento con fármacos experimentales en otro ensayo clínico
    9.Antecedentes o indicios de alguna de las siguientes afecciones:
    Cualquier neoplasia maligna previa (diferente del carcinoma basocelular o carcinoma epidermoide de la piel con el tratamiento adecuado, carcinoma vesical superficial o cualquier otro tipo de carcinoma in situ que actualmente haya remitido completamente) en el plazo de los 5 años previos a la aleatorización
    Angina grave/inestable, infarto de miocardio, insuficiencia cardiaca congestiva sintomática, episodios tromboembólicos arteriales o venosos (por ejemplo, embolia pulmonar, accidente cerebrovascular incluyendo accidentes isquémicos transitorios) o arritmias ventriculares de importancia clínica durante los 6 meses anteriores a la aleatorización
    Hipertensión descontrolada (tensión arterial sistólica ?160 mmHg y/o tensión arterial diastólica ?100 mmHg)
    Trastorno gastrointestinal que afecta a la absorción
    Infección activa, como, por ejemplo el virus de inmunodeficiencia humana (VIH)
    -Cualquier otra afección que, según el investigador, impediría que el paciente cumpliera con los procedimientos del estudio
    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 data for patients without metastasis or death will be censored on the date of the last tumor assessment (or, if no tumor assessment was performed after the baseline visit, at the date of randomization + 1 day).
    Tumor assessments will be performed at baseline and at 16-week intervals from randomization. Imaging studies will include a CT scan of the chest, abdomen, and pelvis, plus a bone scan.
    El criterio de valoración principal del estudio es la supervivencia sin metástasis (MFS), es decir, el tiempo que transcurre desde la aleatorización hasta el primer indicio de metástasis a distancia ósea o en partes blandas detectable con medios radiológicos y confirmada por el BICR (a partir de ahora, mencionada simplemente como ?metástasis?) o muerte por cualquier causa (lo que ocurra primero) + 1 día.
    Las valoraciones del tumor se llevarán a cabo al inicio (cribado) y en intervalos de 16 semanas a partir de ahíla aleatorización. En las pruebas de diagnóstico por imágenes se incluye TC del pecho, abdomen y pelvis, además de una gammagrafía ósea.
    E.5.2Secondary end point(s)
    -Overall Survival (OS)
    -Time to symptomatic progression
    -Time to initiation of cytotoxic chemotherapy
    -Radiographic Progression-Free Survival (PFS)
    -Time to Metastasis (TTM)
    - Supervivencia global (SG)
    - Tiempo transcurrido hasta la progresión sintomática
    - Tiempo transcurrido hasta el inicio de la quimioterapia citotóxica
    - Supervivencia libre de progresión (SLP) con medios radiológicos
    - Tiempo hasta la presencia de metástasis (TTM)
    E.5.2.1Timepoint(s) of evaluation of this end point
    OS (every 4 months via clinic visit or telephone contact)
    Cada 4 meses mediante visitas al centro o contacto telefónico
    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. 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 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 concerned16
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA145
    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
    Czech Republic
    Korea, Republic of
    New Zealand
    Russian Federation
    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
    Patients will remain on study until BICR-confirmed disease progression, development of unacceptable toxicity, or withdrawal of consent.
    If the study is not terminated beforehand per the recommendation of the DMC, the end of trial in all participating countries will be defined as the time at which the secondary endpoint of OS has been met.
    Los pacientes seguirán recibiendo el tratamiento del estudio hasta que el BICR constate la progresión de la enfermedad, se presente toxicidad inaceptable o retire el consentimiento.

    Si el estudio no se concluye antes por recomendación del CVDS, el fin del ensayo en todos los países participantes se definirá como el momento en el que se ha cumplido el criterio de valoración secundario de la SG.
    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 months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months11
    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: 360
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 840
    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 state84
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 640
    F.4.2.2In the whole clinical trial 1200
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients will be followed for at least 28 calendar days after the last dose of study drug. All patients discontinuing study treatment will enter the survival follow-up period and will be followed for the development of symptomatic progression and initiation of subsequent anti-cancer therapies every 4 months until death, loss of follow-up, or withdrawal of consent, whichever comes first.
    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 Decision2013-10-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-10-09
    P. End of Trial
    P.End of Trial StatusOngoing
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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