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    Summary
    EudraCT Number:2016-004907-30
    Sponsor's Protocol Code Number:AG120-C-009
    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:2017-06-22
    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 number2016-004907-30
    A.3Full title of the trial
    A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of AG-120 in Combination with Azacitidine in Subjects ≥ 18 Years of Age with Previously Untreated Acute Myeloid Leukemia with an IDH1 Mutation
    Estudio en fase 3, multicéntrico, doble ciego, aleatorizado y controlado con placebo para evaluar AG-120 en combinación con azacitidina en sujetos de 18 años de edad o más con leucemia mieloide aguda con una mutación de IDH1 sin tratamiento previo
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 study to test the AG-120 in combination with Azacitidine in comparison with the use of Azacitidine alone in patients ≥ 18 Years of Age with previously untreated Acute Myeloid Leukemia with an IDH1 Mutation
    Estudio en fase 3 para evaluar AG-120 en combinación con azacitidina en comparación con el uso de azacitidina sola en pacientes de 18 años de edad o más con leucemia mieloide aguda con una mutación de IDH sin tratamiento previo.
    A.4.1Sponsor's protocol code numberAG120-C-009
    A.5.4Other Identifiers
    Name:IND numberNumber:119341
    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 SponsorAgios 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 supportAgios Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAgios Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointDirector, Scientific Communications
    B.5.3 Address:
    B.5.3.1Street Address88 Sidney Street
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34900834223
    B.5.6E-mailRegistroEspanolDeEstudiosClinicos@druginfo.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1802
    D.3 Description of the IMP
    D.3.1Product nameIvosidenib
    D.3.2Product code AG-120
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIvosidenib
    D.3.9.1CAS number 1448347-49-6
    D.3.9.2Current sponsor codeAG-120
    D.3.9.3Other descriptive nameAG-120
    D.3.9.4EV Substance CodeSUB130391
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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 Vidaza (INN:Azacitidine)
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Ltd
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/07/509
    D.3 Description of the IMP
    D.3.1Product nameAzacitidine
    D.3.4Pharmaceutical form Powder for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAZACITIDINE
    D.3.9.1CAS number 320-67-2
    D.3.9.3Other descriptive nameVidaza, Azadine
    D.3.9.4EV Substance CodeSUB05624MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 placeboTablet
    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
    Acute Myeloid Leukemia with an IDH1 Mutation
    Leucemia mieloide aguda con una mutación de IDH1
    E.1.1.1Medical condition in easily understood language
    Acute myeloid leukemia (cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that build up in the bone marrow) with IDH1 mutation.
    Leucemia mieloide aguda (cáncer en línea mieloide de las células sanguineas, caracterizado por el rápido crecimiento de glóbulos blancos anormales que se acumulan en la médula ósea) con mutación IDH1.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine if treatment with AG-120 in combination with azacitidine significantly prolongs overall survival (OS) compared with placebo administered with azacitidine in subjects with previously untreated isocitrate dehydrogenase 1 mutation-positive (IDH1m) acute myeloid leukemia (AML).
    Determinar si el tratamiento con AG-120 en combinación con azacitidina prolonga significativamente la supervivencia global (SG) en comparación con placebo administrado con azacitidina en pacientes con leucemia mieloide aguda (LMA) con una mutación de la isocitrato deshidrogenasa-1 (IDH1) sin tratamiento previo.
    E.2.2Secondary objectives of the trial
    - To compare event-free survival (EFS) between AG-120 + azacitidine and placebo + azacitidine.
    - To compare the complete remission (CR) rate (based on Investigator-assessed International Working Group [IWG] Response Criteria for AML), between AG-120 + azacitidine and placebo + azacitidine.
    - To compare the CR (based on Investigator-assessed IWG Response Criteria for AML) + complete remission with partial hematologic recovery (CRh) rate between AG-120 + azacitidine and placebo + azacitidine. CRh is defined as a CR with partial recovery of peripheral blood counts (< 5% bone marrow blasts, platelets > 50,000/μL, ANC > 500/μL) and will be derived by the Sponsor.
    - To compare the objective response rate (ORR) between AG-120 + azacitidine and placebo + azacitidine, as assessed by the Investigator.
    - Comparar la supervivencia sin episodios (SSE) entre AG-120 + azacitidina y placebo + azacitidina.
    - Comparar la tasa de remisión completa (RC) (según los Criterios de respuesta de la LMA del IWG [International Working Group, Grupo de trabajo internacional] evaluados por el investigador), entre AG-120 + azacitidina y placebo + azacitidina.
    - Comparar la tasa de RC (según los criterios de respuesta de la LMA del IWG evaluados por el investigador) + remisión completa con recuperación hematológica parcial (RCh) entre AG-120 + azacitidina y placebo + azacitidina. Una RCh se define como una RC con recuperación parcial del hemograma en sangre periférica (proporción de blastos en la médula ósea < 5 %, recuento de plaquetas > 50.000/µl y RAN > 500/μl) y será determinada por el promotor.
    - Comparar la tasa de respuesta objetiva (TRO) entre AG-120 + azacitidina y placebo + azacitidina, según la evaluación del investigador.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must meet all of the following criteria to be eligible for inclusion in the study:
    1. Be ≥ 18 years of age.

    2. Have previously untreated AML, defined according to World Health Organization (WHO) criteria, with ≥ 20% leukemic blasts in the bone marrow. Subjects with extramedullary disease alone (ie, no detectable bone marrow and no detectable peripheral blood AML) are not eligible for the study.

    3. Have an isocitrate dehydrogenase 1 (IDH1) mutation as determined by central laboratory testing (using an investigational polymerase chain reaction [PCR] assay, Abbott RealTime IDH1) in their bone marrow aspirate and/or peripheral blood sample.

    4. Have an ECOG PS score of 0 to 2.

    5. Have adequate hepatic function, as evidenced by:
    a. Serum total bilirubin ≤ 1.5 times the upper limit of normal (× ULN), unless considered to be due to Gilbert’s disease or underlying leukemia, where it must be < 3 × ULN
    b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered to be due to underlying leukemia

    6. Have adequate renal function, as evidenced by serum creatinine ≤ 2.0 × ULN or creatinine clearance > 40 mL/min based on the Cockcroft-Gault glomerular filtration rate.

    7. Have agreed to undergo serial blood and bone marrow sampling.

    8. Be able to understand and willing to sign an informed consent form (ICF).

    9. Be willing to complete QoL assessments during study treatment and at the designated time points following treatment discontinuation.

    10. If female with reproductive potential, must have a negative serum pregnancy test prior to the start of study therapy. Female subjects with reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion or who have not been naturally postmenopausal for at least 24 consecutive months. Females of reproductive potential, as well as fertile men and their female partners of reproductive potential, must agree to use 2 effective forms of contraception (including at least 1 barrier form) from the time of giving informed consent throughout the study and for 90 days (both females and males) following the last dose of study drug(s). Effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal ligation, condoms with spermicide, or male partner sterilization.
    Los pacientes deberán cumplir todos los criterios siguientes para poder participar en el estudio:
    1. Tener una edad mínima de 18 años.
    2. Presentar una LMA no tratada previamente, definida según los criterios de la Organización Mundial de la Salud (OMS), con una proporción de blastos leucémicos en la médula ósea ≥ 20 %. Los pacientes con afectación extramedular exclusivamente (es decir, ausencia de LMA detectable en médula ósea y sangre periférica) no podrán participar en el estudio.
    3. Tener una mutación de la isocitrato deshidrogenasa 1 (IDH1) determinada en los análisis realizados por el laboratorio central (utilizando un ensayo de reacción en cadena de la polimerasa [PCR] en investigación, Abbott RealTime IDH1) en la muestra de aspirado de médula ósea o sangre periférica.
    4. Tener una puntuación de EF del ECOG de 0 a 2.
    5. Presentar una función hepática adecuada, según lo determinado por:
    a. Bilirrubina sérica total ≤ 1,5 veces el límite superior de la normalidad (LSN), a menos que se considere debido a una enfermedad de Gilbert o la leucemia subyacente, en cuyo caso debe ser < 3 veces el LSN.
    b. Aspartato aminotransferasa (AST), alanina aminotransferasa (ALT) y fosfatasa alcalina (FA) ≤ 3,0 veces el LSN, a menos que se consideren debidas a la leucemia subyacente.
    6. Presentar una función renal adecuada, según lo determinado por una creatinina sérica ≤ 2,0 veces el LSN o un aclaramiento de creatinina > 40 ml/min basado en la filtración glomerular calculada con la ecuación de Cockcroft-Gault.
    7. Aceptar someterse a la extracción de muestras seriadas de sangre y médula ósea.
    8. Tener capacidad para entender y estar dispuesto a firmar un documento de consentimiento informado (DCI).
    9. Estar dispuesto a completar las evaluaciones de calidad de vida durante el tratamiento del estudio y en los momentos designados después de la suspensión del tratamiento.
    10. En caso de ser una mujer con capacidad reproductiva, dar negativo en una prueba de embarazo en suero realizada antes del comienzo del tratamiento del estudio. Se entiende por mujeres con capacidad reproductiva aquellas sexualmente maduras que no se han sometido a una histerectomía, ovariectomía bilateral u oclusión tubárica o que no hayan pasado la menopausia natural durante al menos 24 meses consecutivos. Las mujeres con capacidad reproductiva, así como los varones fértiles y sus parejas con capacidad reproductiva, deberán comprometerse a usar dos métodos anticonceptivos eficaces (incluido al menos un método de barrera) desde el momento de otorgar el consentimiento informado, durante todo el estudio y hasta 90 días (mujeres y varones) después de la última dosis del fármaco(s) del estudio. Se entiende por métodos anticonceptivos eficaces los siguientes: anticonceptivos hormonales orales, inyectables o en parches, dispositivos intrauterinos, sistemas intrauterinos de liberación de hormonas, ligadura de trompas bilateral, preservativo con espermicida o esterilización de la pareja masculina.
    E.4Principal exclusion criteria
    Subjects who meet any of the following criteria will be excluded from the study:
    1. Are candidates for and willing to receive intensive induction chemotherapy (IC) for their AML.

    2. Have received any prior treatment for AML with the exception of hydroxyurea.

    3. Have received a hypomethylating agent for myelodysplastic syndrome (MDS).

    4. Subjects who had previously received an experimental agent for MDS may not be randomized until a washout period of at least 5 half-lives of the experimental agent has elapsed since the last dose of that agent.

    5. Have received prior treatment with an IDH1 inhibitor.

    6. Have a known hypersensitivity to any of the components of AG-120, matched placebo, or azacitidine.

    7. Are female and pregnant or breastfeeding.

    8. Are taking known strong cytochrome P450 (CYP) 3A4 inducers or sensitive CYP3A4 substrate medications with a narrow therapeutic window, unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing.

    9. Are taking P-glycoprotein (P-gp) transporter-sensitive substrate medications with a narro therapeutic window, unless they can be transferred to other medications within ≥ 5 half-lives prior to administration of study treatment.

    10. Have an active, uncontrolled, systemic fungal, bacterial, or viral infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.

    11. Have a prior history of malignancy other than MDS or myeloproliferative disorder, unless the subject has been free of the disease for ≥ 1 year prior to the start of study treatment. However, subjects with the following history/concurrent conditions or similar indolent cancer are allowed to participate in the study:
    a. Basal or squamous cell carcinoma of the skin
    b. Carcinoma in situ of the cervix
    c. Carcinoma in situ of the breast
    d. Incidental histologic finding of prostate cancer

    12. Have had significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association Class III or IV congestive heart failure, myocardial infarction, unstable angina, and/or stroke.

    13. Have a heart-rate corrected QT interval using Fridericia’s method (QTcF) ≥ 470 msec or any other factor that increases the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome). Subjects with prolonged QTcF interval in the setting of bundle branch block may participate in the study.

    14. Have an active viral infection caused by human immunodeficiency virus, hepatitis B virus, or hepatitis C virus that cannot be controlled by treatment.

    15. Have dysphagia, short-gut syndrome, gastroparesis, or any other condition that limits the ingestion or gastrointestinal absorption of orally administered drugs.

    16. Have uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg).

    17. Have clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid during Screening is only required if there is a clinical suspicion of CNS involvement by leukemia during Screening.

    18. Have immediate, life-threatening, severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or sepsis, and/or disseminated intravascular coagulation.

    19. Have any other medical or psychological condition deemed by the Investigator to be likely to interfere with the subject’s ability to give informed consent or participate in the study.
    Se excluirá del estudio a los pacientes que cumplan alguno de los criterios siguientes:
    1. Ser candidatos y estar dispuestos a someterse a quimioterapia de inducción (QI) intensiva para la LMA.
    2. Haber recibido cualquier tratamiento previo para la LMA, a excepción de hidroxicarbamida.
    3. Haber recibido un fármaco hipometilante por un síndrome mielodisplásico (SMD).
    4. Los pacientes que hayan recibido un fármaco experimental por SMD no podrán ser aleatorizados hasta que haya transcurrido un período de lavado equivalente a, como mínimo, cinco semividas del fármaco experimental desde la última dosis de dicho fármaco.
    5. Haber recibido tratamiento previo con un inhibidor de IDH1.
    6. Tener hipersensibilidad conocida a cualquiera de los componentes de AG-120, placebo equivalente o azacitidina.
    7. Ser mujer y estar embarazada o en período de lactancia.
    8. Estar tomando inductores potentes de la enzima 3A4 del citocromo P450 (CYP) o medicamentos que sean sustratos sensibles de la enzima CYP3A4 con un margen terapéutico estrecho, a menos que puedan pasar a recibir otros fármacos en un plazo equivalente a, como mínimo, cinco semividas antes de la administración del tratamiento del estudio.
    9. Estar tomando medicamentos que sean sustratos sensibles del transportador glucoproteína P (gp-P) con un margen terapéutico estrecho, a menos que puedan pasar a recibir otros fármacos en un plazo equivalente a, como mínimo, cinco semividas antes de la administración del tratamiento del estudio.
    10. Tener una infección micótica, bacteriana o vírica sistémica, activa y no controlada sin mejoría a pesar de recibir antibióticos, antivirales u otro tratamiento adecuado.
    11. Tener antecedentes de neoplasias malignas diferentes de SMD o trastorno mieloproliferativo, a menos que el paciente se haya mantenido sin enfermedad durante un mínimo de un año antes del comienzo del tratamiento del estudio. Sin embargo, podrán participar en el estudio los pacientes que tengan antecedentes o presencia concomitante de las siguientes enfermedades o un cáncer inactivo similar:
    a. Carcinoma basocelular o espinocelular de piel.
    b. Carcinoma in situ de cuello uterino.
    c. Carcinoma in situ de mama.
    d. Hallazgos histológicos accidentales de cáncer de próstata.
    12. Haber presentado una cardiopatía activa importante en los seis meses previos al comienzo del tratamiento del estudio, entre otras, insuficiencia cardíaca congestiva en clase III o IV según la New York Heart Association (NYHA), infarto de miocardio, angina de pecho inestable o ictus.
    13. Presentar un intervalo QT corregido por la frecuencia cardíaca con la fórmula de Fredericia (QTcF) ≥ 470 ms u otros factores que aumenten el riesgo de sufrir una prolongación del intervalo QT o episodios arrítmicos (por ejemplo, insuficiencia cardíaca, hipopotasemia o antecedentes familiares de síndrome del intervalo QT prolongado). Los pacientes con una prolongación del intervalo QTcF en el contexto de un bloqueo de rama podrán participar en el estudio.
    14. Tener una infección vírica activa causada por el virus de la inmunodeficiencia humana, virus de la hepatitis B o virus de la hepatitis C que no pueda ser controlada con tratamiento.
    15. Presentar disfagia, síndrome del intestino corto, gastroparesia u otra enfermedad que limite la ingestión o absorción gastrointestinal de fármacos administrados por vía oral.
    16. Presentar hipertensión arterial no controlada (presión arterial [PA] sistólica > 180 mm Hg o PA diastólica > 100 mm Hg).
    17. Presentar síntomas clínicos indicativos de una leucemia del sistema nervioso central (SNC) activa o una leucemia del SNC confirmada. Solo se exigirá una evaluación del líquido cefalorraquídeo durante la selección en caso de sospecha clínica de afectación del SNC por la leucemia durante la selección.
    18. Tener complicaciones inmediatas, potencialmente mortales y graves de la leucemia, como hemorragia no controlada, neumonía con hipoxia o sepsis o coagulación intravascular diseminada.
    19. Presentar cualquier otro trastorno médico o psicológico que, según el investigador, es probable que altere la capacidad del paciente para otorgar su consentimiento informado para participar en el estudio.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is OS.
    La variable principal es la supervivencia global (SG).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time from date of randomization to the date of death due to any cause.
    Tiempo transcurrido entre la fecha de aleatorización y la fecha de la muerte por cualquier causa.
    E.5.2Secondary end point(s)
    • EFS, defined as the time from randomization until the occurrence of death from any cause, disease relapse after remission or MLFS, progressive disease, or failure to achieve CR or CRi (including CRp) at 24 weeks, whichever occurs first, based on responses assessed by the Investigator. Remission is defined as CR or CRi (including CRp). If a subject fails to achieve CR or CRi (including CRp) at 24 weeks, the subject will be considered as an EFS event at that time. Event-free survival will be censored in the event of initiation of a new anticancer therapy should it occur prior to any EFS event.
    • CR rate (CR defined as bone marrow blasts < 5% and no Auer rods, absence of extramedullary disease, ANC > 1.0 × 10 9 /L [1000/µL], platelet count ≥ 100 × 10 9 /L [100,000/µL], and independence of red cell transfusions)
    • CR + CRh rate (CRh defined as a CR with partial recovery of peripheral blood counts [< 5% bone marrow blasts, platelets > 50,000/µL, ANC > 500/µL]); CRh is to be derived by the Sponsor
    • ORR, defined as the rate of CR, CRi (including CRp), PR, and MLFS
    - SSE, definida como el tiempo transcurrido entre la aleatorización y la aparición de muerte por cualquier causa, recidiva de la enfermedad tras una remisión o ESLM, progresión de la enfermedad o imposibilidad de alcanzar una RC o RCi (incluida RCp) a las 24 semanas, lo que ocurra antes, según las respuestas evaluadas por el investigador. La remisión se define como RC o RCi (incluida RCp). Si un paciente no logra una RC o RCi (incluida RCp) a las 24 semanas, se le considerará un episodio de SSE en ese momento. La SSE se censurará en caso de comienzo de un nuevo tratamiento antineoplásico, siempre que tenga lugar antes de cualquier episodio de SSE.
    - Tasa de RC (RC definida como: proporción de blastos en la médula ósea < 5 % con ausencia de bastones de Auer, ausencia de afectación extramedular, RAN > 1,0 × 109/l [1000/µl], recuento de plaquetas ≥ 100 × 109/l [100.000/µl] e independencia de transfusiones de eritrocitos).
    - Tasa de RC + RCh (RCh definida como una RC con recuperación parcial del hemograma en sangre periférica [proporción de blastos en la médula ósea < 5 %, recuento de plaquetas > 50.000/µl, RAN > 500/μl]); la RCh será determinada por el promotor.
    - TRO, definida como la tasa de RC, RCi (incluida RCp), RP y ESLM.
    E.5.2.1Timepoint(s) of evaluation of this end point
    EFS- Time from randomization until the occurrence of death from any cause, disease relapse after remission, progressive disease, or treatment failure, whichever occurs first, based on responses assessed by the Investigator.
    CR rate - defined as bone marrow blasts < 5% and no Auer rods, absence of extramedullary disease, ANC > 1.0 × 109/L [1000/μL], platelet count ≥ 100 × 109/L [100,000/μL], and independence of red cell transfusions.
    CR + CRh rate - CR with partial recovery of peripheral blood counts [<5% bone marrow blasts, platelets > 50,000/µL, ANC > 500/µL]
    ORR - rate of CR, CRi (including CRp), PR, and MLFS
    SSE-Tiempo transcurrido entre la aleatorización y la aparición de muerte por cualquier causa, recidiva de la enfermedad tras una remisión, progresión de la enfermedad o fracaso del tratamiento, lo que ocurra antes, según las respuestas evaluadas por el investigador.
    -Tasa de RC-definida como: proporción de blastos en la médula ósea < 5 % con ausencia de bastones de Auer, ausencia de afectación extramedular, RAN > 1,0 × 109/l [1000/µl], recuento de plaquetas ≥ 100 × 109/l [100.000/µl] e independencia de transfusiones de eritrocitos.
    - Tasa de RC + RCh- RC con recuperación parcial del hemograma en sangre periférica [proporción de blastos en la médula ósea < 5 %, recuento de plaquetas > 50.000/µl, RAN > 500/μl]).
    - TRO- tasa de RC, RCi (incluida RCp), RP y ESLM.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group 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) Yes
    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 concerned23
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA107
    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
    Czech Republic
    France
    Germany
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    Poland
    Russian Federation
    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
    End of Study is defined as the time at which all subjects have died, discontinued the study, are lost to follow-up, or have withdrawn consent or when the Sponsor ends the study.
    El final del estudio se define como el momento en el que todos los pacientes hayan fallecido, se hayan retirado del estudio, se hayan perdido para el seguimiento o hayan retirado su consentimiento o cuando el promotor finalice el estudio.
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months2
    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: 168
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 224
    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 state52
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 245
    F.4.2.2In the whole clinical trial 392
    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)
    Release into standard of care.
    Seguimiento según práctica clinica habitual.
    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 Decision2017-09-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-21
    P. End of Trial
    P.End of Trial StatusOngoing
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