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    Summary
    EudraCT Number:2015-003951-23
    Sponsor's Protocol Code Number:AG-221-AML-005
    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:2016-04-20
    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 number2015-003951-23
    A.3Full title of the trial
    A Phase 1b/2 Open-Label, Randomized Study of 2 Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine: Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus SC Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia Harboring an IDH1 or an IDH2 Mutation, Respectively, Who Are Not Candidates to Receive Intensive Induction Chemotherapy
    ESTUDIO DE FASE IB/II, ABIERTO Y ALEATORIZADO, DE DOS FÁRMACOS DIRIGIDOS CONTRA LA ISOCITRATO DESHIDROGENASA (IDH) MUTADA COMBINADOS CON AZACITIDINA: AG 120 ORAL MÁS AZACITIDINA SUBCUTÁNEA Y AG 221 ORAL MÁS AZACITIDINA SUBCUTÁNEA, EN SUJETOS CON LEUCEMIA MIELOIDE AGUDA RECIÉN DIAGNOSTICADA PORTADORES DE UNA MUTACIÓN IDH1 O IDH2 RESPECTIVAMENTE, QUE NO SEAN CANDIDATOS A RECIBIR QUIMIOTERAPIA DE INDUCCIÓN INTENSIVA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to evaluate the safety and effectiveness of a combination of either AG-120 or AG-221 tablets with azacitidine injections in patients with newly diagnosed Acute Myeloid Leukemia (AML) and who have mutations in enzymes isocitrate dehydrogenase 1 or 2 (IDH 1 or IDH2) and are not candidates to receive intensive induction chemotherapy.
    Estudio para evaluar la seguridad y eficacia de la combinación comprimidos de AG-120 o AG-221 con azacitidina inyectada, en pacientes con leucemia mieloide aguda (LMA) recién diagnosticada , que tienen mutaciones en las enzimas isocitrato deshidrogenasa 1 o2 ( IDH1 o IDH2) y que no sean candidatos a recibir quimioterapia de inducción intensiva.
    A.4.1Sponsor's protocol code numberAG-221-AML-005
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02677922
    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 organisationCelgene Corporation
    B.5.2Functional name of contact pointClinicalTrialDisclosure
    B.5.3 Address:
    B.5.3.1Street Address9225 Indian Creek Parkway, Suite 900
    B.5.3.2Town/ cityOverland Park, Kansas
    B.5.3.3Post code66210
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34914229000
    B.5.5Fax number+19132660394
    B.5.6E-mailClinicalTrialDisclosure@celgene.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAG-221
    D.3.2Product code AG-221
    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 INNAG-221 mesylate
    D.3.9.2Current sponsor codeAG-221
    D.3.9.3Other descriptive nameAG-221
    D.3.9.4EV Substance CodeSUB123982
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 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.3.1Product nameAG-221
    D.3.2Product code AG-221
    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 INNAG-221 mesylate
    D.3.9.2Current sponsor codeAG-221
    D.3.9.3Other descriptive nameAG-221
    D.3.9.4EV Substance CodeSUB123982
    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.IMP: 3
    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.3.1Product nameAG-221
    D.3.2Product code AG-221
    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 INNAG-221 mesylate
    D.3.9.2Current sponsor codeAG-221
    D.3.9.3Other descriptive nameAG-221
    D.3.9.4EV Substance CodeSUB123982
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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: 4
    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.3.1Product nameAG-120
    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 INNAG-120
    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: 5
    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.3.1Product nameAG-120
    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 INNAG-120
    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: 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 Vidaza 25mg/ml powder for suspension for injection
    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.3.2Product code L01BC07
    D.3.4Pharmaceutical form Powder for suspension 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 INNAZACITIDINE
    D.3.9.1CAS number 320-67-2
    D.3.9.4EV Substance CodeSUB05624MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Newly diagnosed acute myeloid leukemia (AML) habouring an isocitrate dehydrogenase 1 (IDH1) or an isocitrate dehydrogenase 2 (IDH2) mutation, respectively, who are not candidates to receive intensive induction chemotherapy (IC)
    Leucemia mieloide aguda (LMA) recién diagnosticada con mutaciones en las enzimas isocitrato deshidrogenasa 1 ( IDH1) o isocitrato deshidrogenasa 2 (IDH2), que no sean candidatos a recibir quimioterapia de inducción intensiva
    E.1.1.1Medical condition in easily understood language
    Treatment of subjects with newly diagnosed AML that have mutations in enzymes isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) and who are not candidates to receive intensive induction chemotherapy
    tratamientpo sujetos con LMA recién diagnosticada que tienen mutaciones en enzimas isocitrato deshidrogenasa 1 o 2 y que no sean candidatos a recibir quimioterapia de inducción intensiva
    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 19.0
    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
    Ph Ib: - To assess the safety and tolerability of the combination treatments of oral AG-120 + subcutaneous (SC) azacitidine and oral AG-221 + SC azacitidine in subjects with newly diagnosed acute myeloid leukemia (AML) harboring an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive induction chemotherapy (IC).
    - To establish the recommended Phase 2 dose (RP2D) of oral AG-120 and oral AG-221 when administered with SC azacitidine.
    Ph II: - To assess the efficacy of the combination treatments of oral AG-120 + SC azacitidine and oral AG-221 + SC azacitidine compared with SC azacitidine alone in subjects with newly diagnosed AML harboring an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive IC.
    Fase Ib:
    Evaluar la seguridad y la tolerabilidad de los tratamientos combinados de AG 120 oral más azacitidina subcutánea (s.c.) y de AG 221 oral más azacitidina s.c. en sujetos con LMA recién diagnosticada portadores de una mutación IDH1 o IDH2, respectivamente, que no sean candidatos a recibir quimioterapia de inducción intensiva.
    Establecer la dosis recomendada para la fase II (DRF2) del AG-120 oral y el AG-221 oral cuando se administran junto con azacitidina s.c.
    Fase II:
    Evaluar la eficacia de los tratamientos combinados de AG 120 oral más azacitidina s.c. y de AG 221 oral más azacitidina s.c., en comparación con la azacitidina s.c. en monoterapia, en sujetos con LMA recién diagnosticada portadores de una mutación IDH1 o IDH2, respectivamente, que no sean candidatos a recibir quimioterapia de inducción intensiva.
    E.2.2Secondary objectives of the trial
    Ph Ib: - To assess the preliminary efficacy of the combination treatments of oral AG-120 + SC azacitidine and oral AG-221 + SC azacitidine in subjects with newly diagnosed AML harboring an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive IC.
    Ph II: - To evaluate the safety of oral AG-120 and oral AG-221 when administered with SC azacitidine.
    - To characterize the pharmacokinetics (PK) of oral AG-120 and AG-221 when administered in combination with SC azacitidine.
    - To evaluate the effect of oral AG-120 and oral AG-221 when administered with SC azacitidine versus SC azacitidine alone on health-related quality-of-life (HRQoL) outcomes.
    FaseIb: Evaluar la eficacia preliminar de los tratamientos combinados de AG 120 oral más azacitidina s.c. y de AG 221 oral más azacitidina s.c. en sujetos con LMA recién diagnosticada portadores de una mutación IDH1 o IDH2, respectivamente, que no sean candidatos a recibir quimioterapia de inducción intensiva.
    Fase II:
    Evaluar la seguridad del AG 120 oral y el AG 221 oral cuando se administran junto con azacitidina s.c.
    Determinar la farmacocinética (FC) del AG 120 oral y el AG 221 cuando se administran en combinación con azacitidina s.c.
    Evaluar el efecto del AG 120 oral y el AG 221 oral cuando se administran junto con azacitidina s.c., en comparación con la azacitidina s.c. en monoterapia, sobre los resultados de la calidad de vida relacionada con la salud (CVRS).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject is > = 18 years of age at 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 previously untreated, primary (ie, de novo) or secondary (progression of MDS or myeloproliferative neoplasms [MPN], or therapy-related) AML according to the
    WHO classification (Appendix B) with > = 20% leukemic blasts in the bone marrow:
    a. Have an IDH1 or IDH2 gene mutation (R132, R140, or R172)
    - IDH mutational status will be assessed locally; for sites without local testing capabilities, a referral lab will be identified.
    b. By the investigator?s assessment who are not candidates to receive intensive IC.
    5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1
    or 2 (Appendix D).
    6. Subject has adequate organ function defined as:
    - Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) < = 3 x ULN, unless
    considered due to leukemic organ involvement.
    - Serum total bilirubin < 1.5 x ULN. Higher levels are acceptable if these can be attributed to ineffective erythropoiesis, 3 times the upper limit of normal for Gilbert?s syndrome (eg, a gene mutation in
    UGT1A1), or leukemic organ involvement.
    - Serum creatinine < 2 x ULN or creatinine clearance > 30 mL/min based on the
    Cockroft-Gault glomerular filtration rate (GFR) estimation:
    (140 - Age) x (weight in kg) x (0.85 if female) / 72 x serum creatinine
    7. Agree to serial bone marrow aspirate/biopsies.
    8. Females of childbearing potential (FCBP)* may participate, providing they meet the
    following conditions:
    - Agree to abstain from sexual intercourse or to use at least two highly effective contraceptive methods (eg, combined [containing estrogen and progestogen] or progestogen alone associated with inhibition of ovulation, oral, injectable, patch, or implantable hormonal contraceptive; bilateral tubal occlusion; intra-uterine device; intrauterine hormone-releasing system; or male partner sterilization) at screening and throughout the study, and for 4 months following the last study treatment ; and
    - Have a negative serum ?-subunit of human chorionic gonadotropin (?-hCG)
    pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
    - Have a negative serum ?-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to the start of study treatment in the Treatment Period (note that the screening serum pregnancy test can be used as the test prior to the start of study treatment in the Treatment Period if it is performed within the 72-hour timeframe).
    9. Male subjects (with a female partner of childbearing potential who must agree to conditions in criterion 8) must agree to abstain from sexual intercourse or agree to the use of at least 2 highly effective contraceptive methods at screening and throughout the course of the study and should avoid fathering a child during the course of the study and for 4 months following the last study treatment (6 months following the last dose of azacitidine in Canada).
    1.Edad mínima de 18 años en el momento de firmar el documento de consentimiento informado (DCI).
    2.Comprender y firmar voluntariamente el DCI antes de realizar las evaluaciones y procedimientos relacionados con el estudio.
    3.Estar dispuesto y tener capacidad de cumplir el calendario de visitas del estudio y los demás requisitos del protocolo.
    4.Presentar una LMA no tratada primaria (es decir, de novo) o secundaria (progresión de un SMD o una neoplasia mieloproliferativa [NMP], o debida a un tratamiento previo) conforme a la clasificación de la OMS de la LMA (apéndice B) con al menos un 20% de blastos leucémicos en la médula ósea:
    a. Tener una mutación del gen IDH1 o IDH2 (R132, R140 o R172)
    -El estado de mutación del gen IDH se evaluará en un laboratorio local; cuando los centros carezcan de capacidades para realizar análisis locales, se designará a un laboratorio de referencia. .
    b.No ser candidato a recibir quimioterapia de inducción según lo determinado por el investigador.
    5.Estado funcional de 0, 1 ó 2 según el Eastern Cooperative Oncology Group (ECOG) (apéndice D).
    6.Tener una función orgánica adecuada, definida como:
    -Aspartato aminotransferasa /transaminasa glutámico oxalacética sérica (AST/SGOT) y alanina aminotransferasa sérica (ALT/SGPT) < = 3 veces el LSN, a menos que se atribuya a una afectación orgánica de la leucemia.
    -Bilirrubina total sérica < 1,5 veces el LSN. Son aceptables valores más altos si se atribuyen a eritropoyesis ineficaz, 3 veces por encima del límite superior de normalidad para el síndrome de Gilbert (por ejemplo, mutación del gen UGT1A1) o a una afectación orgánica de la leucemia.
    -Creatinina sérica < 2 veces el LSN o aclaramiento de creatinina ? 30 ml/min calculado a partir de la fórmula de filtración glomerular (FG) de Cockroft Gault: (140 ? edad) ? (peso en kg) ? (0,85 en las mujeres)/72 x creatinina sérica
    7.Aceptar someterse a aspirados o biopsias seriadas de médula ósea.
    8.Podrán participar mujeres en edad fértil (MEF)*, siempre que cumplan las siguientes condiciones:
    -Comprometerse a no mantener relaciones sexuales o a utilizar al menos dos métodos anticonceptivos muy eficaces (p. ej., combinados [con estrógeno y progesterona) o con solo progesterona para la inhibición de la ovulación, anticonceptivos hormonales orales, inyectables, transdérmicos o implantables, ligadura de trompas bilateral, dispositivo intrauterino, sistema intrauterino de liberación de hormonas, o esterilización de la pareja masculina) durante la selección, a lo largo de todo el estudio y hasta 4 meses después de la última dosis del tratamiento del estudio; y
    -Tener un resultado negativo en la prueba de embarazo (subunidad ? de la gonadotropina coriónica humana [ß hCG]; sensibilidad de al menos 25 mUI/ml) en suero en el período de selección; y
    -Tener un resultado negativo en la prueba de embarazo (?hCG; sensibilidad de al menos 25 mUI/ml) en suero en las 72 horas previas al comienzo del tratamiento del estudio en el período de tratamiento (la prueba de embarazo en suero que se efectúe durante la selección servirá como prueba previa al inicio del tratamiento del estudio en el período de tratamiento siempre que se haya llevado dentro del margen de 72 horas).
    9.Los varones (con pareja femenina en edad fértil que debe comprometerse a cumplir las condiciones establecidas en el criterio 8) deberán abstenerse** de mantener relaciones sexuales o aceptar el uso de métodos anticonceptivos muy eficaces durante la selección, a lo largo de todo el estudio) y hasta 4 meses después de la última dosis del tratamiento del estudio (6 meses después de la última dosis de azacitidina en Canadá).
    E.4Principal exclusion criteria
    1. Subject is suspected or proven to have acute promyelocytic leukemia based on
    morphology, immunophenotype, molecular assay, or karyotype (Appendix B).
    2. Subject has AML secondary to chronic myelogenous leukemia (CML; Appendix C).
    3. Subject has received a targeted agent against an IDH1 or IDH2 mutation.
    4. Subject has received prior systemic anticancer therapy, HSCT, or radiotherapy for AML.
    Note that hydroxyurea is allowed prior to the start of study treatment for the control of
    leukocytosis in subjects with white blood cell (WBC) counts > 30 x 10^9/L (however,
    hydroxyurea should not be given within 72 hours prior to and after administration of
    azacitidine). For subjects with secondary AML (eg, MDS or MPN) treatment for prior
    cancer is not exclusionary; full treatment information will be collected within the CRF.
    5. Subject has received prior treatment with azacitidine or decitabine for MDS.
    6. Subject has or is suspected of having central nervous system (CNS) leukemia.
    Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is
    suspected during screening.
    7. Subject has immediate life-threatening, severe complications of leukemia such as
    uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
    intravascular coagulation.
    8. Subject has significant active cardiac disease within 6 months prior to the start of study
    treatment, including New York Heart Association (NYHA) class III or IV congestive
    heart failure (Appendix E); acute coronary syndrome (ACS); and/or stroke; or left
    ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated
    acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment.
    9. Subject has prior history of malignancy, other than MDS, MPN, or AML, 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 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, node,
    metastasis clinical staging system)
    10. Subject is known seropositive for or has active viral infection with human immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
    11. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other
    conditions that limit the ingestion or gastrointestinal absorption of drugs administered
    orally
    12. Subject has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or
    diastolic BP > 100 mmHg)
    13. Subject is taking the following sensitive CYP substrate medications that have a narrow
    therapeutic range are excluded from the study unless the subject can be transferred to
    other medications at least 5 half-lives prior to the start of study treatment: phenytoin
    (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and
    tizanidine (CYP1A2) (Appendix K).
    14. Subject is taking the breast cancer resistance protein (BCRP) transporter-sensitive
    substrate rosuvastatin; subject should be excluded from the study unless he/she can be
    transferred to other medications at least 5 half-lives prior to the start of study treatment
    (Appendix L).
    15. Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as
    ongoing signs/symptoms related to the infection without improvement despite
    appropriate antibiotics, antiviral therapy, and/or other treatment).
    16. Subject has known or suspected hypersensitivity to any of the components of study
    therapy.
    17. Subject is taking medications that are known to prolong the QT interval (Appendix M)
    unless he/she can be transferred to other medications within > = 5 half-lives prior to the start of study treatment. (If equivalent medication is not available, QTc will be closely monitored as defined in Section 8.1.)
    18. Subject has QTc interval (ie, Fridericia?s correction [QTcF]) > = 450 ms or other factors
    that increase the risk of QT prolongation or arrhythmic events (eg, heart failure,
    hypokalemia, family history of long QT interval syndrome) at screening.
    19. Female subject who is pregnant or lactating.
    20. Subject has any significant medical condition, laboratory abnormality, or psychiatric
    illness that would prevent the subject from participating in the study.
    21. Subject has any condition, including the presence of laboratory abnormalities, that places the subject at unacceptable risk if he/she were to participate in the study.
    22. Subject has any condition that confounds the ability to interpret data from the study.
    1. Presentar una leucemia promeliocítica aguda presunta o confirmada por la morfología, el inmunofenotipo, el análisis molecular o el cariotipo (Apéndice B).2. Presentar una LMA secundaria a una leucemia mielógena crónica (LMC, Apéndice C).
    3. Haber recibido un fármaco dirigido contra la IDH1 o la IDH2 mutada.4. Haber recibido con anterioridad un tratamiento antineoplásico sistémico, TCMH o radioterapia para la LMA. Se permite la administración de hidroxiurea antes de empezar el tratamiento del estudio para controlar la leucocitosis en pacientes con cifras de leucocitos > 30 x 109/l (sin embargo, no debe administrarse en las 72 horas previas y posteriores a la administración de azacitidina). En los sujetos con LMA secundaria (es decir, SMD o NMP), el tratamiento recibido para el cáncer previo no es excluyente; se recogerá toda la información relativa al tratamiento en el CRD.5. Haber recibido con anterioridad tratamiento con azacitidina o decitabina para un SMD. 6. Leucemia del sistema nervioso central (SNC) presunta o confirmada. Durante la selección se hará un análisis del líquido cefalorraquídeo únicamente si se sospecha afectación del SNC por leucemia.7. Complicaciones graves y potencialmente mortales de la leucemia, como hemorragia no controlada, neumonía con hipoxia o shock, y/o coagulación intravascular diseminada.8. Cardiopatía activa significativa en los 6 meses anteriores al comienzo del tratamiento del estudio, incluida la insuficiencia cardíaca congestiva de clase III o IV según la New York Heart Association (NYHA) (Apéndice E); síndrome coronario agudo (SCA); y/o accidente cerebrovascular; o fracción de eyección del ventrículo izquierdo (FEVI) < 40% por ecocardiograma (Eco) o ventriculografía isotópica (MUGA) obtenidos en los 28 días anteriores al comienzo del tratamiento del estudio.9. Antecedentes de neoplasia maligna distinta de SMD, NMP o LMA, a menos que el paciente se haya mantenido sin enfermedad durante al menos un año antes del comienzo del tratamiento del estudio. Sin embargo, podrán participar los pacientes con los siguientes antecedentes o enfermedades concomitantes:-Carcinoma basocelular o espinocelular de piel.-Carcinoma cervicouterino in situ.?Carcinoma in situ de mama.-Identificación histológica fortuita de un cáncer de próstata (T1a o T1b según el sistema de estadificación clínica TNM [tumor, ganglios, metástasis]).10. Seropositividad o infección activa por el virus de la inmunodeficiencia humana (VIH) o infección activa por el virus de la hepatitis B (VHB) o el virus de la hepatitis C (VHC).11. Disfagia, síndrome de intestino corto, gastroparesia u otras enfermedades que limiten la ingestión o la absorción en el tubo digestivo de los fármacos administrados por vía oral.12. Hipertensión arterial no controlada (presión arterial [PA] sistólica > 180 mm Hg o diastólica > 100 mm Hg).13.Los pacientes en tratamiento con sustratos sensibles del CYP que tienen un índice terapéutico estrecho quedarán excluidos del estudio salvo que se les pueda cambiar la medicación al menos 5 semividas antes del comienzo del tratamiento del estudio: fenitoína (CYP2C9), S mefenitoína (CYP2C19), tioridazina (CYP2D6), teofilina y tizanidina (CYP1A2) (Apéndice K).14. Los pacientes en tratamiento con rosuvastatina, un sustrato sensible del transportador proteína de resistencia al cáncer de mama (BCRP), quedarán excluidos del estudio salvo que se les pueda cambiar la medicación al menos 5 semividas antes del comienzo del tratamiento del estudio (Apéndice L).15. Infección micótica, bacteriana, o viral sistémica, activa y no controlada (definida como la presencia de signos y síntomas persistentes relacionados con la infección que no mejoran a pesar del tratamiento apropiado con antibióticos, antivirales o cualquier otro tratamiento).16. Hipersensibilidad presunta o confirmada a cualquier componente del tratamiento del estudio.17. Tratamiento con medicamentos que se sabe que prolongan el intervalo QT (Apéndice M) salvo que se les pueda cambiar la medicación al menos 5 semividas antes del comienzo del tratamiento del estudio. (En el caso de que no haya un medicamento equivalente, se hará una vigilancia estrecha del intervalo QTc conforme lo definido en el apartado 8.1).18. Intervalo QTc (con corrección según la fórmula de Fridericia [QTcF]) > = 450 ms u otros factores que aumentan el riesgo de prolongación del intervalo QT, o episodios arrítmicos (por ejemplo, insuficiencia cardíaca, hipopotasemia, antecedentes familiares de síndrome del intervalo QT prolongado) en el período de selección.19. Mujeres embarazadas o lactantes.20. Cualquier enfermedad, anomalía analítica o trastorno psiquiátrico importante que impida al sujeto participar en el estudio.21. Toda situación, incluida la presencia de anomalías analíticas, que entrañe un riesgo inaceptable para el sujeto en caso de participar en el estudio.22. Presencia de cualquier situación que altere la capacidad de interpretar los datos del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Ph Ib:
    1. Recommended Phase 2 Dose - Review of dose-limiting toxicities (DLTs), safety, and possibly, PK / pharmacodynamic, biomarker, and preliminary efficacy data by DRT.
    2. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.
    Ph II:
    3. Overall Response Rate - Rate of MLFS + CR + CRi + CRp + PR according to modified IWG AML response criteria (Appendix F).
    Fase Ib
    1.Dosis recomendada para la fase II Revisión, por parte del ERD, de los datos sobre toxicidad limitante de la dosis (TLD), seguridad y, posiblemente, FC/farmacodinamiaFD, biomarcadores y eficacia preliminar.
    2.Seguridad y tolerabilidad Tipo, frecuencia, gravedad e intensidad de los AA y su relación con el tratamiento del estudio.
    Fase II
    3.Tasa de respuesta global Tasa de ALM + RC + RCi + RCp + RP conforme a los criterios de respuesta modificados del IWG para la LMA (Apéndice F).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Ph Ib:
    1. Recommended Phase 2 Dose - Approximately 8 months
    2. Safety / tolerability - Approximately 13 months
    Ph II:
    3. Overall Response Rate - Approximately 30 months
    FASE Ib
    1. Dosis recomendada para la fase II-Aproximadamente 8 meses
    2. Seguridad y tolerabilidad-Aproximadamente 13 meses
    Fase II
    3. Tasa de respuesta global -Aproximadamente 30 meses
    E.5.2Secondary end point(s)
    Ph Ib:
    1. Overall Response Rate - Rate of MLFS + CR + CRi + CRp + PR according to modified IWG AML response criteria (Appendix F).
    2. Pharmacodynamics (Exploratory) - To evaluate the pharmacodynamics of oral AG-120 + SC azacitidine and oral AG-221 + SC azacitidine when administered in combination in this population.
    Ph II:
    3. Event-Free Survival - Time from randomization to documented morphologic relapse, progression according to modified IWG AML response criteria (Appendix F), or death from any cause, whichever occurs first.
    4. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.
    5. Complete remission rate - Rate of CR according to modified IWG AML response criteria (Appendix F).
    6. Hematologic improvement rate - Rate of HI-N + HI-P + HI-E according to IWG MDS HI criteria (Appendix G).
    7. Duration of Response - Time from the first documented MLFS/CR/CRi/CRp/PR to documented morphologic relapse, progression according to modified IWG AML response criteria (Appendix F), or death due to any cause, whichever occurs first
    8. Overall Survival - Time from randomization to death due to any cause.
    9. One-year survival - The probability of survival at 1 year from randomization
    10. PK parameters - Plasma concentrations and pharmacokinetic parameters of AG-120 or AG-221.
    11. HRQoL outcomes - European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC QLQ-C30) (Appendix N) and EuroQoL Group EQ-5D-5L instrument (Appendix O)
    12. Healthcare resource utilization (Exploratory) - Information about all resource use
    (eg, hospitalization)
    13. Days alive and out of hospital (Exploratory)- Measurement of days without hospitalization
    14. Pharmacodynamics (Exploratory) - Evaluation of 2-HG and ?-KG levels in plasma and bone marrow.
    Evaluate methylation in PB and/or transcription in BM.
    15. Correlative studies (Exploratory) - Evaluation of molecular, cellular and metabolic markers which may be predictive of antitumor activity and/or resistance.
    Evaluation of minimal residual disease (MRD), to assess IDH1 and IDH2 variant allele fraction (VAF) in blood and bone marrow cells.
    Evaluation of changes in cellular differentiation and changes in histone and deoxyribonucleic acid (DNA) methylation profiles of IDH1 and IDH2 mutated leukemic cells as well as wildtype IDH leukemic cells induced by oral AG-120 and oral AG-221 when
    administered with SC azacitidine.
    FASE Ib
    1. Tasa de respuesta global-Tasa de ALM + RC + RCi + RCp + RP conforme a los criterios de respuesta modificados del IWG para la LMA (Apéndice F).
    2. Farmacodinámica Evaluar la farmacodinamiaFD del AG 120 oral + azacitidina s.c. y del AG 221 oral + azacitidina s.c. cuando se administran en combinación en esta población.
    FASE II
    3. Supervivencia sin acontecimientos- Tiempo transcurrido desde la aleatorización hasta la recidiva morfológica documentada, la progresión conforme a los criterios de respuesta modificados del IWG para la LMA (Apéndice F) o la muerte por cualquier causa, lo que ocurra antes
    4. Seguridad y tolerabilidad- Tipo, frecuencia, gravedad e intensidad de los AA y su relación con el tratamiento del estudio.
    5.Tasa de remisión completa-Tasa de RC conforme a los criterios de respuesta modificados del IWG para la LMA (Apéndice F).
    6. Tasa de mejoría hematológica-Tasa de MH N + MH P + MH E conforme a los criterios de MH del IWG para el SMD (Apéndice G).
    7. Duración de la respuesta-Tiempo transcurrido desde la primera ALM/RC/RCi/RCp/RP documentada hasta la recidiva morfológica documentada, la progresión conforme a los criterios de respuesta modificados del IWG para la LMA (Apéndice F) o la muerte por cualquier causa, lo que ocurra antes
    8. Supervivencia global -Tiempo transcurrido desde la aleatorización hasta la fecha de muerte por cualquier causa.
    9. Supervivencia a un año-Probabilidad de seguir con vida un año después de la aleatorización
    10. Parámetros de FC-Concentración plasmática y parámetros farmacocinéticos de AG 120 o AG 221.
    11. Resultados de CVRS-- Cuestionario sobre calidad de vida de la Organización Europea para la Investigación y el Tratamiento del Cáncer (EORTC QLQ C30) (Apéndice N) e instrumento EQ 5D 5L del Grupo EuroQoL (Apéndice O) 12. Utilización de recursos sanitarios (Exploratorio)-Información sobre toda la utilización de recursos (p. ej., hospitalización)
    13. Días de vida sin hospitalización (Exploratorio) Determinación de los días sin hospitalización
    14. Farmacodinámica (Exploratorio)- Evaluación de la concentración de 2 HG y ? KG en plasma y médula ósea. Evaluar la metilación en SP y/o la transcripción en MO.
    15. Pruebas relacionadas ( Exploratory)
    Evaluación de los marcadores moleculares, celulares y metabólicos que puedan ser predictivos de la actividad antitumoral o la resistencia.
    Evaluación de la enfermedad residual mínima (ERM) para determinar la frecuencia de variantes alélicas (FVA) del IDH1 y el IDH2 en células sanguíneas y de médula ósea.
    Evaluación de las variaciones de la diferenciación celular y las variaciones de los perfiles de metilación de histonas y ADN en las células leucémicas con mutación IDH1 o IDH2, y en las células leucémicas sin mutación del IDH, inducidas por el AG 120 oral y el AG 221 oral cuando se administran junto con azacitidina s.c.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Ph Ib: All secondary and Exploratory objectives - Approximately 13 months
    Ph II: All secondary and Exploratory objectives - Approximately 30 months
    FASE Ib: todos Los objetivos secundarios y exploración - aproximadamente 13 meses
    FASE II: todos los objetivos secundarios y exploración - aproximadamente 30 meses
    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 Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose escalation
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open 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 trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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
    Canada
    France
    Germany
    Italy
    Korea, Republic of
    Netherlands
    Portugal
    Spain
    Switzerland
    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
    The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment 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 pre-specified in the protocol, whichever is the later date.
    El final del ensayo se define como la fecha de la última visita del último sujeto que finalice el seguimiento posterior al tratamiento o la fecha de recepción de los últimos datos correspondientes al último sujeto que sean necesarios para los análisis principales, secundarios o exploratorios, tal como se establece en el protocolo, la que sea posterior.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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: 52
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 122
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 83
    F.4.2.2In the whole clinical trial 174
    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)
    The subject's treatment after ending participation in the trial will be at the discretion of the treating physician.
    El tratamiento del sujeto al final de su participación en el ensayo será según criterio del médico que lo ateinde
    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 Decision2016-07-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-09
    P. End of Trial
    P.End of Trial StatusOngoing
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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