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    Summary
    EudraCT Number:2017-003190-34
    Sponsor's Protocol Code Number:ACE-536-MDS-002
    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:2018-08-07
    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 number2017-003190-34
    A.3Full title of the trial
    A Phase 3, Open -label, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) versus Epoetin alfa for the Treatment of Anemia due to IPSS-R Very Low, Low or Intermediate Risk Myelodysplastic Syndromes (MDS) in ESA Naïve Subjects who require Red Blood Cell Transfusions.
    Estudio de fase 3, abierto y aleatorizado para comparar la eficacia y la seguridad de luspatercept (ACE-536) frente a epoetina alfa para el tratamiento de la anemia debida a síndromes mielodisplásicos (SMD) de riesgo muy bajo, bajo o intermedio según la clasificación IPSS-R en pacientes sin tratamiento previo con estimulantes de la eritropoyesis que necesitan transfusiones de glóbulos rojos.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 study to see the benefit and safety of Luspatercept in comparison with Epoetin Alfa to treat anaemia due to very low, low or intermediate risk Myelodysplastic Syndromes (MDS) in people who have not taken erythropoiesis-stimulating agents (ESA's) before and who require red blood cell transfusions.
    Estudio de fase 3 para ver la eficacia y la seguridad de luspatercept en comparación con epoetina alfa para el tratamiento de la anemia debida a síndromes mielodisplásicos (SMD) de riesgo muy bajo, bajo o intermedio en pacientes sin tratamiento previo con estimulantes de la eritropoyesis (EE) que necesitan transfusiones de glóbulos rojos.
    A.3.2Name or abbreviated title of the trial where available
    The Commands Trial
    A.4.1Sponsor's protocol code numberACE-536-MDS-002
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCelgene Corporation
    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 supportCelgene Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPPD
    B.5.2Functional name of contact pointPPD Project Manager
    B.5.3 Address:
    B.5.3.1Street Addressvia San Bovio, 3
    B.5.3.2Town/ citySan Felice Segrate, Milan
    B.5.3.3Post code20090
    B.5.3.4CountryItaly
    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/3/14/1331
    D.3 Description of the IMP
    D.3.1Product nameLuspatercept
    D.3.2Product code ACE-536
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLuspatercept
    D.3.9.1CAS number 1373715-00-4
    D.3.9.2Current sponsor codeACE-536
    D.3.9.3Other descriptive nameLuspatercept
    D.3.9.4EV Substance CodeSUB189400
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number37.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1331
    D.3 Description of the IMP
    D.3.1Product nameLuspatercept
    D.3.2Product code ACE-536
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLuspatercept
    D.3.9.1CAS number 1373715-00-4
    D.3.9.2Current sponsor codeACE-536
    D.3.9.3Other descriptive nameLuspatercept
    D.3.9.4EV Substance CodeSUB189400
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number87.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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: 3
    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 Eprex
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag Ltd
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 Solution for infusion in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEpoetin Alfa
    D.3.9.1CAS number 113427-24-0
    D.3.9.4EV Substance CodeSUB06575MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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: 4
    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 Eprex
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag Ltd
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 Solution for infusion in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEpoetin Alfa
    D.3.9.1CAS number 113427-24-0
    D.3.9.4EV Substance CodeSUB06575MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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: 5
    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 Eprex
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag Ltd
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 Solution for infusion in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEpoetin Alfa
    D.3.9.1CAS number 113427-24-0
    D.3.9.4EV Substance CodeSUB06575MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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: 6
    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 Eprex
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag Ltd
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 Solution for infusion in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEpoetin Alfa
    D.3.9.1CAS number 113427-24-0
    D.3.9.4EV Substance CodeSUB06575MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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: 7
    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 Eprex
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag Ltd
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 Solution for infusion in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEpoetin Alfa
    D.3.9.1CAS number 113427-24-0
    D.3.9.4EV Substance CodeSUB06575MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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: 8
    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 Eprex
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag Ltd
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 Solution for infusion in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEpoetin Alfa
    D.3.9.1CAS number 113427-24-0
    D.3.9.4EV Substance CodeSUB06575MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Myelodysplastic syndrome (MDS)
    Síndrome mielodisplásico (SMD)
    E.1.1.1Medical condition in easily understood language
    Umbrella term for disorders of the bone marrow, leading to a reduced number of red blood cells.
    Término general para los trastornos de la médula ósea, que conducen a un número reducido de glóbulos rojos.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10068361
    E.1.2Term MDS
    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
    The primary objective of the study is to evaluate the efficacy of luspatercept compared with epoetin alfa for the treatment of anemia due to IPSS-R very low, low, or intermediate risk MDS in ESA naïve subjects who require RBC transfusions.
    El objetivo principal del estudio es evaluar la eficacia de luspatercept en comparación con epoetina alfa en el tratamiento de la anemia debida a SMD de riesgo muy bajo, bajo o intermedio según el IPSS-R en pacientes sin tratamiento previo con EE que necesitan transfusiones de eritrocitos.
    E.2.2Secondary objectives of the trial
    • To assess the safety and efficacy of luspatercept compared to epoetin alfa
    • To assess health-related quality of life (HRQoL) and anemia outcome measures (ie, the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire [EORTC QLQ-C30] and the Functional Assessment of Cancer Therapy - Anemia (FACT-An) questionnaire for subjects treated with luspatercept compared to epoetin alfa
    • To evaluate population pharmacokinetics and exposure-response relationships for luspatercept in MDS subjects
    • Evaluar la seguridad y la eficacia de luspatercept en comparación con epoetina alfa.
    • Evaluar la calidad de vida relacionada con la salud (CVRS) y los criterios de valoración de la anemia (es decir, cuestionario de calidad de vida de la European Organization for Research and Treatment of Cancer [QLQ-C30 de la EORTC] y cuestionario FACT-An (evaluación funcional del tratamiento del cáncer-anemia) en
    los pacientes tratados con luspatercept en comparación con epoetina alfa.
    • Evaluar la farmacocinética de la población y las relaciones exposición-respuesta para luspatercept en sujetos con SMD
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).
    2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
    3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
    4. Subject has a documented diagnosis of MDS according to WHO 2016 classification that meets IPSS R classification of very low, low, or intermediate risk disease, and < 5% blasts in bone marrow.
    5. Subject has an endogenous serum erythropoietin (sEPO) level of < 500 U/L.
    6. Subject requires RBC transfusions, as documented by the following criteria:
    • Average transfusion requirement of 2 - 6 units/8 weeks of pRBCs confirmed for a minimum of 8 weeks immediately preceding randomization.
    Hemoglobin levels at the time of or within 7 days prior to administration of a RBC transfusion must have been ≤ 9.0 g/dL with symptoms of anemia (or ≤ 7 g/dL in the absence of symptoms) in order for the transfusion to be counted towards meeting eligibility criteria. Red blood cell transfusions administered when Hgb levels were > 9.0 g/dL (or > 7 g/dL in the absence of symptoms) and/or RBC transfusions administered for elective surgery, infections or bleeding events will not qualify as a required transfusion for the purpose of meeting eligibility criteria or stratification.
    The hemoglobin level after the last RBC transfusion prior to randomization must be < 11.0 g/dL (centrally or locally analyzed).
    7. Subject has Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.
    8. Females of childbearing potential (FCBP), defined as a sexually mature woman who:
    1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months), must:
    •Have two negative pregnancy tests as verified by the investigator prior to starting study therapy (unless the screening pregnancy test was done within 72 hours of W1D1). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment.
    •If sexually active, agree to use, and be able to comply with, highly effective contraception without interruption, 5 weeks prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy.
    9. Male subjects must:
    •Practice true abstinence (which must be reviewed prior to each IP administration or on a monthly basis [eg, in the event of dose delays]) or agree to use a condom (latex or non-latex, but not made out of natural [animal] membrane) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks following investigational product discontinuation, even if he has undergone a successful vasectomy.
    1. Edad mínima de 18 años en el momento de firmar el documento de consentimiento informado (DCI).
    2. Comprensión y firma voluntaria del DCI antes de realizar las evaluaciones y procedimientos relacionados con el estudio.
    3. Disponibilidad y capacidad de cumplir el calendario de visitas del estudio y los demás requisitos del protocolo.
    4. Diagnóstico documentado de SMD según la clasificación de la OMS de 2016 que cumpla la clasificación IPSS R (Greenberg, 2012) de enfermedad de riesgo muy bajo, bajo o intermedio y:
    < 5% de blastos en la médula ósea.
    5. Concentración sérica de eritropoyetina (sEPO) endógena < 500 U/l.
    6. Necesidad de transfusiones de eritrocitos, documentada mediante los criterios siguientes :
    - Necesidad media de transfusiones de 2-6 unidades/8 semanas de concentrados de hematíes confirmada durante un mínimo de 8 semanas inmediatamente anteriores a la aleatorización.
    La concentración de hemoglobina en el momento de la administración de una transfusión de eritrocitos o en los 7 días previos deberá haber sido <= 9,0 g/dl con síntomas de anemia (o <= 7 g/dl en ausencia de síntomas) para poder contabilizar la transfusión a efectos de cumplimiento de los criterios de elegibilidad. Las transfusiones de eritrocitos administradas con una concentración de Hb > 9,0 g/dl (o > 7 g/dl en ausencia de síntomas) o las administradas por cirugía programada, infecciones o episodios hemorrágicos no se considerarán transfusiones necesarias a efectos de cumplimiento de los criterios de elegibilidad o de la estratificación.
    La concentración de hemoglobina después de la última transfusión de eritrocitos antes de la aleatorización debe ser < 11,0 g/dl (mediante análisis centralizado o local).
    7. Puntuación del Eastern Cooperative Oncology Group (ECOG) de 0, 1 o 2.
    8. Las mujeres en edad fértil (MEF), definidas como mujeres sexualmente maduras que:
    1) no se hayan sometido a una histerectomía u ovariectomía bilateral o 2) no hayan llegado a la menopausia natural (la amenorrea tras el tratamiento del cáncer no descarta la posibilidad de concebir) durante al menos 24 meses consecutivos (es decir, hayan tenido la menstruación en algún momento de los 24 meses consecutivos previos), tendrán que:
    - Haber obtenido un resultado negativo en dos pruebas de embarazo, según lo verificado por el investigador antes de iniciar el tratamiento del estudio (a menos que la prueba de embarazo de selección se haya realizado en las 72 horas previas al D1S1). También deberán acceder a someterse a pruebas de embarazo periódicamente durante el estudio y después de finalizar el tratamiento del estudio.
    - En caso de ser sexualmente activas, comprometerse a utilizar y ser capaces de cumplir con el uso de métodos anticonceptivos muy eficaces sin interrupción, desde 5 semanas antes del inicio de la administración del producto en investigación, durante el tratamiento del estudio (incluidas las interrupciones de la administración) y hasta 12 semanas después de la suspensión del tratamiento del estudio.
    9. Los varones tendrán que:
    - Practicar abstinencia completa (que deberá revisarse antes de cada administración del producto en investigación o mensualmente [p. ej., si hay aplazamientos de dosis] o comprometerse a utilizar preservativo (de látex o no, pero no fabricado con membrana natural [animal]) durante las relaciones sexuales con una mujer embarazada o en edad fértil mientras participen en el estudio, durante las interrupciones de la administración y hasta 12 semanas, como mínimo, después de la suspensión del producto en investigación, aunque se haya sometido a una vasectomía con éxito.
    E.4Principal exclusion criteria
    1.Subject with the any of the following prior treatments:
    •Erythropoiesis-stimulating agents (ESAs)
    •Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), unless given for treatment of febrile neutropenia
    •Disease modifying agents (eg, immune-modulatory drug [IMiDs such as lenalidomide]
    Except if the subject received ≤ 1 week of treatment with a disease modifying agent ≥ 8 weeks from randomization, at the investigator’s discretion.
    •Hypomethylating agents
    Subjects may be randomized at the investigator’s discretion contingent that the subject received no more than 2 doses of HMA. The last dose must be ≥ 8 weeks from the date of randomization.
    •Luspatercept (ACE-536) or sotatercept (ACE-011)
    •Immunosuppressive therapy for MDS
    •Hematopoietic cell transplant
    2.Subject with MDS associated with del(5q) cytogenetic abnormality or MDS unclassifiable (MDS-U) according to WHO 2016 classification.
    3.Subject with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) according to WHO 2016 classification (ie, Chronic myelomonocytic leukemia (CMML), Atypical chronic myeloid leukemia (aCML), BCR-ABL12, Juvenile myelomonocytic leukemia (JMML), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), MDS/MPN unclassifiable.
    4.Subject with secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases.
    5.Subject with known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or hypothyroidism, or any type of known clinically significant bleeding or sequestration. Subject with drug induced anemia (eg, mycophenolate).
    •Iron deficiency to be determined by serum ferritin < 100 µg/L and additional testing if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding capacity ≤ 20%] or bone marrow aspirate stain for iron).
    6.Subject with known history of diagnosis of AML.
    7.Subject receiving any of the following treatment within 8 weeks prior to randomization:
    •Anticancer cytotoxic chemotherapeutic agent or treatment
    •Systemic corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS
    •Iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 weeks prior to randomization
    •Other RBC hematopoietic growth factors (eg, Interleukin-3)
    •Androgens, unless to treat hypogonadism
    •Hydroxyurea
    •Oral retinoids (except for topical retinoids)
    •Arsenic trioxide
    •Interferon and interleukins
    •Investigational drug or device, or approved therapy for investigational use (if 5 times the half-life of the previous investigational drug exceeds 8 weeks, then the time of exclusion should be extended up to 5 times the half-life of the investigational drug)
    8.Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment.
    9.Subject with any of the following laboratory abnormalities:
    •Absolute neutrophil count (ANC) < 500/μL (0.5 x 10^9/L)
    •Platelet count < 50,000/μL (50 x 10^9/L)
    •Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 (via the 4-variable modification of diet in renal disease [MDRD] formula)
    •Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN)
    •Total bilirubin ≥ 2.0 x ULN.
    Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis) or in the presence of known history of Gilbert Syndrome.
    10.Subject with prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed:
    •Basal or squamous cell carcinoma of the skin
    •Carcinoma in situ of the cervix
    •Carcinoma in situ of the breast
    •Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
    11.Subject with major surgery within 8 weeks prior to randomization. Subjects must have completely recovered from any previous surgery prior to randomization.
    12.Subject with history of cerebrovascular accident (including ischemic, embolic, and hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous thrombosis (DVT; including proximal and distal), pulmonary or arterial embolism, arterial thrombosis or other venous thrombosis within 6 months prior to randomization
    Note: prior superficial thrombophlebitis is not an exclusion criterion.

    Further exclusion criteria are noted in the Protocol.
    1.Sujetos con los siguientes tratamientos previos:
    -FEE. -G-CSF o GM-CSF. -Fármacos modificadores de la enfermedad. Salvo que el sujeto haya recibido tratamiento durante <= 1 semana con un fármaco modificador de la enfermedad >= 8 semanas después de la aleatorización, a criterio del investigador. -Fármacos hipometilantes. Los sujetos podrán ser aleatorizados siempre que no hayan recibido más de dos dosis de hipometilantes. La última dosis deberá haberse administrado >= 8 semanas antes de la fecha de aleatorización.- Luspatercept (ACE-536) o sotatercept (ACE-011).-Tratamiento inmunodepresor para el SMD. -Trasplante de células hematopoyéticas. 2.Sujetos con SMD asociado a la anomalía citogenética del(5q) o SMD-NC según la clasificación de la OMS de 2016. 3.Sujetos con neoplasias mielodisplásicas/mieloproliferativas (SMD/NMP). 4.SMD secundario. 5.Sujetos con anemia clínicamente significativa conocida debida a ferropenia, carencia de vitamina B12 o folato, anemia hemolítica autoinmunitaria o hereditaria o hipotiroidismo, o cualquier tipo de hemorragia o secuestro clínicamente significativo. Sujetos con anemia por fármacos. La ferropenia se determinará mediante una ferritina sérica < 100 μg/l y otras pruebas si está clínicamente indicado . 6.Sujetos con antecedentes conocidos de diagnóstico de LMA. 7.Sujetos que reciban cualquiera de los siguientes tratamientos en las 8 semanas previas a la aleatorización: -Quimioterápicos citotóxicos o tratamientos contra el cáncer. -Corticoides sistémicos, excepto en los sujetos tratados con una dosis estable o descendente durante >= 1 semana antes de la aleatorización por procesos médicos distintos del SMD. -Quelantes del hierro. -Otros factores de crecimiento hematopoyéticos de eritrocitos. -Andrógenos, excepto para tratar el hipogonadismo. -Hidroxicarbamida. -Retinoides orales (excepto retinoides tópicos). -Trióxido de arsénico. -Interferón e interleucinas. -Fármaco o dispositivo en investigación o tratamiento aprobado para uso experimental.
    8.Sujetos con hipertensión no controlada, definida como elevaciones repetidas de la presión arterial sistólica (PAS) >= 150 mm Hg o la presión arterial diastólica (PAD) >= 100 mm Hg a pesar de un tratamiento adecuado. 9.Sujetos con alguna de las alteraciones analíticas siguientes: -Recuento absoluto de neutrófilos (RAN) < 500/μl (0,5 x 109/l). -Recuento de plaquetas < 50.000/μl (50 x 109/l). -Filtración glomerular estimada (FGe) < 40 ml/min/1,73 m2. -Aspartato aminotransferasa/transaminasa glutamicooxaloacética sérica (AST/SGOT) o alanina aminotransferasa/transaminasa glutamicopirúvica sérica (ALT/SGPT) >= 3,0 veces el límite superior de la normalidad (LSN). -Bilirrubina total >= 2,0 veces el LSN. 10.Sujetos con antecedentes de neoplasias malignas distintas del SMD, a menos que se hayan mantenido sin enfermedad durante un mínimo de cinco años. Podrán participar los sujetos con lo siguientes: -Carcinoma basocelular o espinocelular de piel. -Carcinoma in situ de cuello uterino. -Carcinoma in situ de mama. -Hallazgo histológico casual de cáncer de próstata (T1a o T1b según el sistema de estadificación clínica TNM. 11.Sujetos con intervención de cirugía mayor en las 8 semanas previas a la aleatorización. 12.Sujetos con antecedentes de accidente cerebrovascular,accidente isquémico transitorio, trombosis venosa profunda, embolia pulmonar o arterial, trombosis arterial u otra trombosis venosa en los 6 meses previos a la aleatorización. 13.Crisis epilépticas de nueva aparición o mal controladas en las 12 semanas previas a la aleatorización. 14.Sujetos con los siguientes trastornos cardíacos en los 6 meses previos a la aleatorización: infarto de miocardio, angina de pecho no controlada, insuficiencia cardíaca aguda descompensada o insuficiencia cardíaca en clase III-IV o arritmia cardíaca no controlada. Sujetos con una fracción de eyección conocida < 35%, confirmada mediante un ECG o una MUGA realizados en los 6 meses previos a la aleatorización. 15.Sujetos con infección micótica, bacteriana o vírica sistémica y no controlada. 16.Sujetos con infección conocida por el VIH, signos conocidos de hepatitis B infecciosa activa o signos conocidos de hepatitis C activa. 17.Sujetos con antecedentes de reacciones alérgicas o anafilácticas graves o hipersensibilidad a proteínas recombinantes o excipientes del luspatercept. 18.Sujetos con hipersensibilidad conocida al principio activo o a cualquiera de los excipientes de la epoetina alfa. 19.Sujetos con antecedentes de APSR o anticuerpos contra la eritropoyetina. 20.Embarazo o lactancia materna. 21.Sujetos con cualquier proceso médico, anomalía analítica o enfermedad psiquiátrica importante o que se consideren vulnerables. 22.Sujetos con cualquier circunstancia que entrañe un riesgo inaceptable para ellos en caso de participar en el estudio. 23.Sujetos con cualquier circunstancia o medicamento concomitante que altere la capacidad de interpretar los datos del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of subjects who are RBC transfusion free over the first 24 weeks from randomization
    Proporción de sujetos que no reciben transfusión de glóbulos rojos durante las primeras 24 semanas desde la aleatorización
    E.5.1.1Timepoint(s) of evaluation of this end point
    Randomization through week 24
    Aleatorización hasta la semana 24
    E.5.2Secondary end point(s)
    1. Proportion of subjects achieving HI-E over any consecutive 56-day period.
    2. Proportion of subjects achieving ≥ 1.5 g/dL mean increase in hemoglobin over the first 24 weeks from randomization compared to baseline in the absence of RBC transfusions.
    3. Proportion of subjects achieving HI-E over any consecutive 56-day period.
    4. Proportion of subjects achieving ≥ 1.5 g/dL mean increase in hemoglobin over any consecutive 24-week period compared to baseline in the absence of RBC transfusions.
    5. Time from first dose to first onset of achieving ≥ 1.5 g/dL increase in hemoglobin over any consecutive 56-day period in the absence of RBC transfusions.
    6. Maximum duration of achieving ≥ 1.5 g/dL increase in hemoglobin for subjects who achieve mean hemoglobin increase ≥ 56 days in the absence of RBC transfusions.
    7. Maximum duration of RBC transfusion independence for subjects who achieve RBC TI ≥ 24 weeks.
    8. Proportion of subjects who are RBC transfusion free over a consecutive 84-day period.
    9. Maximum duration of RBC transfusion independence for subjects who achieve RBC TI ≥ 84 days.
    10. Time from randomization to first onset of transfusion independence ≥ 84 days.
    11. Time from randomization to first transfusion on treatment.
    12. Total number of RBC units transfused on treatment.
    13. Mean change in total pRBC units transfused over a rolling 8-week period.
    14. Proportion of subjects who are RBC transfusion independent during Weeks 4-24.
    15. Proportion of subjects who are RBC transfusion free for a consecutive 24-week period in the first 48 weeks from Randomization.
    16. Evaluation of EORTC QLQ-C30 score and FACT-An.
    17. Type, frequency, severity of AEs and relationship of AEs to luspatercept/epoetin alfa.
    18. A Population PK model that describes the PK exposure data of luspatercept and associated variability. Exposure-response relationship for selected endpoints of efficacy and safety.
    19. Frequency of antidrug antibodies and effects on efficacy, or safety, or PK.
    20. Number and percentage of subjects progressing to AML; time to AML progression.
    21. Time from date of randomization to death due to any cause.
    22. Evaluation of biomarkers such as TGF-ß superfamily members (eg, GDF11) and other molecules that may potentially impact luspatercept efficacy, predict response or relapse, help to better understand MOA and/or provide further prognostic classification of MDS subtypes. Molecular markers (eg, SF3B1) include evaluation of MDS-associated gene mutations and their impact on drug efficacy, clinical response or relapse, disease progression, drug MOA and prognostication of MDS.
    23. Evaluation of healthcare resource use (eg, hospitalization) associated with investigational product (IP) during study.
    24. Description of QUALMS-P and Treatment Satisfaction.
    1. Proporción de sujetos que logren una MH-E durante cualquier período de 56 días consecutivos
    2. Proporción de sujetos que logren un aumento medio de la hemoglobina ≥ 1,5 g/dl durante las primeras 24 semanas desde la aleatorización en comparación con el momento basal en ausencia de transfusiones de eritrocitos.
    3.Proporción de sujetos que logren una MH-E durante cualquier período de 56 días consecutivos.
    4. Proporción de sujetos que logren un aumento medio de la hemoglobina ≥ 1,5 g/dl durante cualquier período de 24 semanas consecutivas en comparación con el momento basal en ausencia de transfusiones de eritrocitos.
    5.Tiempo transcurrido entre la primera dosis y la primera aparición de un aumento de la hemoglobina ≥ 1,5 g/dl durante cualquier período de 56 días consecutivos en ausencia de transfusiones de eritrocitos.
    6.Duración máxima de la consecución de un aumento de la hemoglobina ≥ 1,5 g/dl en los sujetos que logren un aumento de la hemoglobina medio durante ≥ 56 días en ausencia de transfusiones de eritrocitos.
    7.Duración máxima de la independencia de transfusiones de eritrocitos en los sujetos que logren la ITE durante ≥ 24 semanas.
    8. Proporción de sujetos sin transfusiones de eritrocitos durante un período de 84 días consecutivos.
    9.Duración máxima de la independencia de transfusiones de eritrocitos en los sujetos que logren la ITE durante ≥ 84 días.
    10.Tiempo transcurrido entre la aleatorización y la primera aparición de independencia de transfusiones ≥ 84 días.
    11.Tiempo transcurrido entre la aleatorización y la primera transfusión durante el tratamiento.
    12.Número total de unidades de eritrocitos transfundidas durante el tratamiento.
    13.Variación media de las unidades totales de concentrados de eritrocitos transfundidas durante un período de 8 semanas renovable.14. Proporción de sujetos con independencia de transfusiones de eritrocitos durante las semanas 4-24
    15.Proporción de sujetos sin transfusiones de eritrocitos durante un período de 24 semanas consecutivas en las primeras 48 semanas desde la aleatorización
    16.Evaluación de la puntuación QLQ-C30 del EORTC y FACT-An.
    17.Tipo, frecuencia e intensidad de los AA y su relación con luspatercept/epoetina alfa.
    18.Modelo de FC poblacional que describe los datos de exposición FC de luspatercept y la variabilidad asociada. Relación exposición-respuesta para determinados criterios de valoración de la eficacia y la seguridad.
    19.Frecuencia de anticuerpos contra el fármaco y efectos sobre la eficacia, seguridad o FC.
    20Número y porcentaje de sujetos con progresión a LMA; tiempo transcurrido hasta la progresión a LMA.
    21.Tiempo transcurrido entre la aleatorización y la muerte por cualquier causa.
    22.Evaluación de biomarcadores como miembros de la superfamilia del TGF-ß (p. ej., GDF11) y otras moléculas que podrían influir en la eficacia de luspatercept, predecir la respuesta o la recidiva, ayudar a conocer mejor el mecanismo de acción o proporcionar una clasificación pronóstica más detallada de los subtipos de SMD. Los marcadores moleculares (p. ej., SF3B1) comprenden la evaluación de mutaciones génicas asociadas al SMD y su efecto sobre la eficacia del fármaco, la respuesta clínica o la recidiva, la progresión de la enfermedad, el mecanismo de acción del fármaco y el pronóstico del SMD.
    23.Evaluación del uso de recursos sanitarios (p. ej., hospitalización) asociado al producto en investigación durante el estudio.
    24.Descripción de QUALMS-P y satisfacción con el tratamiento.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1, 2, 5, 8, 10, 12, 13: Randomization through week 24
    3, 4, 5, 13, 15: Randomization thought week 48
    6, 7, 9, 11: Randomization through End of Treatment
    14: week 4 through week 24
    17: Screening though 42 days post last dose; randomization thorough week 48
    18, 19: Randomization through 1-year post first dose
    20, 21: randomization though at least 3 year post last dose
    22, 23: Baseline through end of treatment
    16, 24: Screening through end of treatment
    1, 2, 5, 8, 10, 12, 13: Aleatorización hasta la semana 24
    3, 4, 5, 13, 15: Aleatorización hasta la semana 48
    6, 7, 9, 11: Aleatorización hasta la semana el fin de tratamiento
    14: Semana 4 hasta la semana 24
    17: Visita de seleccion hasta 42 días tras la última dosis; randomizacion hasta la semana 48
    18, 19: Aleatorización hasta 1 año tras la primera dosis
    20, 21: Aleatorización hasta al menos 3 años tras la ultima dosis.
    22, 23: Visita basal hasta el fin de tratamiento
    16, 24: Visita de seleccion hasta fin del tratamiento
    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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarkers
    Biomarcadores
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA111
    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
    Belgium
    Canada
    Czech Republic
    France
    Germany
    Italy
    Japan
    Lithuania
    Netherlands
    Poland
    Portugal
    Russian Federation
    Spain
    Sweden
    Switzerland
    Taiwan
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Either the date of the last visit of the last subject to complete the post-treatement follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date.
    La fecha de la última visita del último sujeto para completar el seguimiento posterior al tratamiento, o la fecha de recepción del último dato del último paciente que se requiere para el análisis primario, secundario y / o exploratorio, tal y como se especifica en el protocolo, la fecha que ocurra más tarde.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months0
    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: 103
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 247
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 255
    F.4.2.2In the whole clinical trial 350
    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)
    Subjects who have received at least one dose of IP should undergo EOT and 42d Follow-up evaluations for 8wks after last dose of IP or the EOT Visit, whichever occurs later.Subjects will be followed every 12wks for the first 3yrs from the date of last dose of IP or from the date of the EOT Visit(whichever is later)& every 6mths thereafter for monitoring&overall survival for min 5yrs from the date of last dose of IP unless the subject withdraws from the study. Subjects will receive SoC post study.
    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 Decision2019-05-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-29
    P. End of Trial
    P.End of Trial StatusOngoing
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