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    Summary
    EudraCT Number:2015-005732-18
    Sponsor's Protocol Code Number:DU176b-A-U157
    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:2016-05-17
    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 number2015-005732-18
    A.3Full title of the trial
    A Phase 1, Open-Label, Single-dose, Non-randomized Study to Evaluate Pharmacokinetics and Pharmacodynamics of Edoxaban in Pediatric Patients
    Estudio en fase I, en abierto, de dosis única y no randomizado para evaluar la farmacocinética (FC) y la farmacodinámica (FD) de edoxabán en pacientes pediátricos
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of an oral anticoagulant (Edoxaban) in children
    Estudio de un anticoagulante oral (Edoxabán) en niños
    A.4.1Sponsor's protocol code numberDU176b-A-U157
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02303431
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/302/2015
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorDaiichi Sankyo , Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDaiichi Sankyo Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationReal Regulatory Limited
    B.5.2Functional name of contact pointClinical Trial Information Contact
    B.5.3 Address:
    B.5.3.1Street AddressHudson House, 8 Tavistock Street, Covent Garden
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeWC2E 7PP
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0044(0)2031787140
    B.5.6E-maileucta@dsi.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Lixiana (60 mg Film-coated tablet)
    D.2.1.1.2Name of the Marketing Authorisation holderDaiichi Sankyo Europe GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEdoxaban tosylate
    D.3.2Product code DU-176b
    D.3.4Pharmaceutical form Film-coated 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 INNEdoxaban
    D.3.9.1CAS number 480449-70-5
    D.3.9.2Current sponsor codeEdoxaban
    D.3.9.4EV Substance CodeSUB32701
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 Yes
    D.2.1.1.1Trade name Lixiana
    D.2.1.1.2Name of the Marketing Authorisation holderDaiichi Sankyo Europe GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEdoxaban tosylate
    D.3.2Product code DU-176b
    D.3.4Pharmaceutical form Granules for oral suspension
    D.3.4.1Specific paediatric formulation Yes
    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 INNEdoxaban
    D.3.9.1CAS number 480449-70-5
    D.3.9.2Current sponsor codeEdoxaban
    D.3.9.4EV Substance CodeSUB32701
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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 Yes
    D.2.1.1.1Trade name Lixiana (30 mg film-coated tablet)
    D.2.1.1.2Name of the Marketing Authorisation holderDaiichi Sankyo Europe GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEdoxaban tosylate
    D.3.2Product code DU-176b
    D.3.4Pharmaceutical form Film-coated 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 INNEdoxaban
    D.3.9.1CAS number 480449-70-5
    D.3.9.2Current sponsor codeEdoxaban
    D.3.9.4EV Substance CodeSUB32701
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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
    Edoxaban is being investigated for use in pediatric patients who may require anticoagulation therapy.
    Edoxobán está siendo investigado para el uso en pacientes pediaátricos los cuales requieren de terapia anticoagulante.
    E.1.1.1Medical condition in easily understood language
    A study of Edoxaban in children.
    Estudio de Edoxobán en niños.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10010495
    E.1.2Term Congenital heart disease NOS
    E.1.2System Organ Class 100000004850
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10057396
    E.1.2Term Thrombophilia
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To characterize the PK of Edoxaban in pediatric patients following oral single-dose administration.
    ? Caracterizar la FC de edoxabán en pacientes pediátricos tras la administración de una dosis única por vía oral
    E.2.2Secondary objectives of the trial
    - To evaluate the PD effects of edoxaban in pediatric patients following single-dose oral administration
    - To evaluate the safety and tolerability of single-dose oral administration of edoxaban in pediatric patients
    - To assess metabolite exposure (D21-2393, D21-3231, D21-1402, and D21-2135) in pediatric patients
    - To evaluate the palatability (bitterness, sweetness, and overall taste or aroma) of the liquid oral suspension of edoxaban
    ? Evaluar los efectos FD de edoxabán en pacientes pediátricos tras la administración de una dosis única por vía oral.
    ? Evaluar la seguridad y la tolerabilidad de la administración de dosis únicas por vía oral de edoxabán a pacientes pediátricos.
    ? Evaluar la exposición a los metabolitos (D21-2393, D21-3231, D21-1402 y D21-2135) en pacientes pediátricos.
    ? Evaluar la palatabilidad (amargura, dulzura y sabor o aroma generales) de la suspensión líquida oral de edoxabán.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Able to provide written informed assents (patients, when applicable) and ICFs (signed by parent/legal guardian) prior to participating in the study
    2. Male or female patients 0 to < 18 years of age on the day of dosing
    3. Patients 2 to < 18 years of age must have a body mass index (BMI) between the 5th and 95th percentile based on the 2000 CDC Growth Charts7 (the maximum number of patients in each dose group that have a BMI between 85th and 95th percentile should not be more than 2 patients). Patients < 2 years of age must have a body weight between the 5th and 90th percentile based on the 2000 CDC Growth Charts7
    4. Female patients who have had menarche must test negative for pregnancy at screening and check-in
    5. Female patients who have had menarche and are sexually active must use an acceptable contraception method for at least 30 days prior to edoxaban dose
    6. Patients/Legal guardian(s) must agree to food and drug restrictions during the study
    7. Patients must agree to abstain from the use of nonsteroidal anti-inflammatory drugs (such as ibuprofen), and antiplatelet and anticoagulant agents (except for low-dose aspirin) from 24 hours prior to edoxaban dose until after the last PK sample is collected
    8. Patients on low-dose aspirin treatment (1 to 5 mg/kg/day, maximum of 100 mg/day) with an interruption of aspirin 24 hours prior to edoxaban dose and resuming 24 hours after edoxaban dose are permitted to participate in the study per the Investigator?s judgment that this does not place the patients at risk
    9. Patients must agree to abstain from CYP3A4 inhibitors/inducers and P-gp inhibitors/inducers for 14 days prior to the edoxaban dose to until after the last PK sample is collected (See Section 5.2)
    10. Patients must agree to abstain from and/or legal guardians must agree not to give the patient cola, tea, coffee, chocolate, and other caffeinated drinks and food from 48 hours before dose administration through check-out (See Section 5.3 for a complete list)
    11. Other than signs and symptoms characteristic to their disease state, patients are to be in good health as determined by the absence of clinically significant deviations from normal, with respect to medical and surgical history, physical examination, vital signs, and laboratory reports, as deemed by the Investigator and the Sponsor, prior to enrollment
    12. Patients must agree to abstain from and/or legal guardians must agree not to give the patient St. John?s Wort and food/supplement and beverages containing grapefruit, grapefruit juice, and Seville oranges from 14 days before the first dose through the end of the study (See Section 5.3)
    1. Ser capaz de otorgar por escrito asentimientos informados (en el caso de los pacientes, cuando proceda) y DCI (firmado por los padres o el tutor legal) antes de participar en el estudio.
    2. Pacientes de ambos sexos, de 0 a < 18 años de edad el día de la administración.
    3. Los pacientes de 2 a menos de 18 años de edad deben tener un índice de masa corporal (IMC) comprendido entre los percentiles 5 y 95 de las tablas de crecimiento de los CDC estadounidenses (Centers for Disease Control and Prevention) del año 20007 (el número máximo de pacientes de cada grupo de dosis que presente un IMC entre los percentiles 85 y 95 no debe ser superior a 2 pacientes). Los pacientes menores de 2 años deben tener un peso corporal comprendido entre los percentiles 5 y 90 de las tablas de crecimiento de los CDC del año 20007.
    4. Las pacientes que ya hayan tenido la primera menstruación deben dar un resultado negativo en la prueba de embarazo y las revisiones.
    5. Las pacientes que ya hayan tenido la primera menstruación y sean sexualmente activas deben utilizar un método anticonceptivo aceptable durante al menos los 30 días previos a la administración de la dosis de edoxabán.
    6. Los padres o los tutores legales deben aceptar las restricciones alimentarias y toxicológicas durante el estudio.
    7. Los padres deben aceptar abstenerse de usar antinflamatorios no esteroideos (como el ibuprofeno) y antiagregantes plaquetarios y anticoagulantes (a excepción del ácido acetilsalicílico en dosis bajas) desde las 24 horas previas a la administración de la dosis de edoxabán hasta después de la obtención de la muestra de FC.
    8. Aquellos pacientes que estén recibiendo dosis bajas de ácido acetilsalicílico (1-5 mg/kg/día; máximo de 100 mg/día) y que interrumpan la toma de ácido acetilsalicílico en las 24 horas previas a la administración de la dosis de edoxabán, reiniciándola a las 24 horas después de la administración de la dosis de edoxabán, pueden participar en el estudio siempre que el investigador considere que ello no supone un riesgo para el paciente.
    9. Los pacientes deben aceptar abstenerse de tomar inhibidores o inductores de la CYP3A4 y la P-gp durante los 14 días previos a la administración de la dosis de edoxabán hasta después de la obtención de la última muestra de FC (véase el apartado 5.2).
    10. Los pacientes deben aceptar abstenerse de tomar cola, té, café, chocolate u otras bebidas o alimentos que contengan cafeína (y/o sus tutores legales deben aceptar no dar estas bebidas o comidas a los pacientes) desde las 48 horas previas a la administración de la dosis hasta la finalización (consulte una lista completa en el apartado 5.3).
    11. Aparte de los signos y los síntomas característicos de su estado patológico, antes de la inclusión y a juicio del Investigador y del Promotor, los pacientes deben gozar de un buen estado de salud, determinado mediante la ausencia de desviaciones de la normalidad clínicamente significativas, en lo referente a sus antecedentes médicos y quirúrgicos, exploración física, constantes vitales e informes de las pruebas analíticas.
    12. Los pacientes deben aceptar abstenerse de tomar hierba de San Juan y alimentos, complementos y bebidas que contengan pomelo, zumo de pomelo y naranja amarga (y/o los tutores legales deben aceptar abstenerse de dárselos) desde los 14 días previos a la administración de la primera dosis hasta que finalice el estudio (véase el apartado 5.3).
    E.4Principal exclusion criteria
    1. History (within the last 6 months) of abnormal coagulation tests during screening, as defined by local laboratory reference ranges, which are not explained by anticoagulation therapy
    2. Stroke where anticoagulant therapy is contraindicated
    3. Patients with stage 2 hypertension defined as blood pressure confirmed > 99th percentile + 5 mmHg
    4. Patients with renal function less than 50% of normal for age and size as determined by the National Kidney Disease Education Program version of the Schwartz formula8
    5. Actively bleeding or has a high risk of bleeding
    6. Has a currently active gastrointestinal ulceration or a known history of peptic ulcer or gastrointestinal bleeding (including hematemesis, melena, or rectal bleeding including bleeding from hemorrhoids) within the previous 6 months
    7. Has known diabetic retinopathy
    8. Has thrombocytopenia at screening (< 20 × 109/L)
    9. Has had other unrelated clinically significant illness within 4 weeks prior to Day 1, predose
    10. Planned invasive procedures during or within 24 hours of study drug administration
    11. Patient is receiving high-dose aspirin concurrently or within 2 weeks prior to dosing
    12. Use of P-gp or CYP 3A4 inhibitors or inducers within 14 days prior to the edoxaban dose and expected to continue through the study duration
    13. Patients with history of major bleeding and/or neurosurgery within 6 months of dosing
    14. Patients with history of major trauma or surgery within the last month
    15. Patients with known malabsorption disorders (e.g., cystic fibrosis or short bowel syndrome)
    16. Hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk or alanine transaminase (ALT) > 5 times the upper limit of normal (ULN) or total bilirubin > 2 times the ULN with direct bilirubin > 20% of the total
    17. Patient is currently enrolled in another investigational device or drug study, or is receiving other investigational agents. Patients must have completed the prior clinical study at least 30 days prior to dosing
    18. Patients of childbearing potential (post-menarche) who are sexually active and are not using approved contraception; who are pregnant (as based on test results); or are breastfeeding
    19. Females with history of abnormal menses, including history of menorrhagia (heavy menstrual bleeding), metrorrhagia, or polymenorrhea
    20. Patient has known sensitivity to the investigational product (IP) or any of its excipients
    21. Positive drug or alcohol screen (excluding cotinine) at screening for patients 12 years of age or older, for newborns and for patients who are being breastfed
    22. Patients who have received a transfusion or any blood products within 30 days prior to the first dose
    23. Any major bleeding during prior anticoagulant therapy
    24. Patients with any condition, that as judged by the Investigator, would place the patient at increased risk of harm if he/she participated in the study
    1. Antecedentes (en los últimos 6 meses) de resultados anómalos de la coagulación sanguínea durante el screening, tal como queda definido en los intervalos de referencia del laboratorio local, cuya explicación no sea el empleo de un tratamiento anticoagulante.
    2. Ictus, para el que el uso de un tratamiento anticoagulante esté contraindicado.
    3. Pacientes que padezcan una hipertensión de estadio 2, definida como una tensión arterial confirmada superior al percentil 99 + 5 mm Hg.
    4. Pacientes que presenten una actividad renal inferior al 50 % de la función normal para la edad y el tamaño, determinada mediante la versión de la fórmula de Schwartz8 del Programa de Educación Nacional sobre la Enfermedad de los Riñones de EE. UU.
    5. Que padezca una hemorragia activa o que presente un riego elevado de hemorragia.
    6. Que padezca una ulceración gastrointestinal activa o presente antecedentes de úlcera gástrica o hemorragia gastrointestinal (incluso hematemesis, melena o rectorragia, lo que incluye los sangrados provocados por las hemorroides) en los 6 meses previos.
    7. Que padezca una retinopatía diabética conocida.
    8. Que padezca una trombocitopenia en el screening (< 20 × 109/l).
    9. Que padezca otras enfermedades clínicamente significativas que no estén relacionadas en las 4 semanas previas al Día 1 (predosis).
    10. Pacientes que tengan planificada una intervención quirúrgica invasiva durante la administración del fármaco del estudio o en las 24 horas previas.
    11. El paciente está recibiendo de forma simultánea dosis elevadas de ácido acetilsalicílico o en las 2 semanas previas a la administración del medicamento.
    12. Uso de inhibidores o inductores de la P-gp o la CYP3A4 en los 14 días previos a la administración de la dosis de edoxabán y esté previsto que siga tomándolos durante la duración del estudio.
    13. Pacientes con antecedentes de hemorragias mayores y/o neurocirugías en los 6 meses previos a la administración del medicamento.
    14. Pacientes con antecedentes de traumas o cirugía mayores en el último mes.
    15. Pacientes que padezcan trastornos conocidos de malabsorción (p. ej., fibrosis quística o síndrome del intestino corto).
    16. Hepatopatía relacionada con la coagulopatía que conlleve un riesgo importante de hemorragia desde el punto de vista clínico, una concentración de alanina-aminotransferasa (ALAT) > 5 veces el límite superior de normalidad (LSN) o una concentración de bilirrubina total > 2 veces el LSN, con una concentración de bilirrubina directa > 20 % del total.
    17. El paciente está participando actualmente en otro estudio clínico con dispositivos o fármacos o está recibiendo otros medicamentos en fase de investigación clínica. Los pacientes deben haber finalizado su participación en el estudio anterior con un mínimo de 30 días de antelación a la administración de la dosis.
    18. Las pacientes en edad fértil (posmenarquia) que sean sexualmente activas y que no empleen un método anticonceptivo autorizado; las pacientes embarazadas (según los resultados del análisis); o las pacientes que estén en el período de lactancia.
    19. Las mujeres que tengan antecedentes de desarreglos menstruales, incluso los antecedentes de menorragia (sangrados menstruales abundantes), metrorragia o polimenorrea.
    20. Paciente que padezca una hipersensibilidad conocida al medicamento en investigación (MI) o a alguno de sus excipientes.
    21. Un resultado positivo en el análisis de estupefacientes o alcohol (a excepción de la cotinina) en el screening en el caso de pacientes de 12 años de edad o en adelante, neonatos y pacientes que se encuentren en el período de lactancia.
    22. Pacientes que hayan recibido una transfusión o algún hemoderivado en los 30 días previos a la administración de la primera dosis.
    23. Cualquier hemorragia importante durante un tratamiento anticoagulante previo.
    24. Pacientes que presenten cualquier trastorno que, a juicio del Investigador, pudiera aumentar el riesgo de lesión del paciente si este participa en el estudio.
    E.5 End points
    E.5.1Primary end point(s)
    - The PK endpoints will include PK parameters such as apparent systemic clearance (CL/F) and apparent volume of distribution (V/F). If data permit, derived PK parameters such as AUC and metabolite/parent ratios for AUCs will also be estimated.
    Parámetros farmacocinéticos como el aclaramiento sistémico aparente (Cl/F), el volumen de distribución aparente (V/F).Si los datos lo permiten, también se calcularán los parámetros FC derivados como el ABC y los cocientes metabolito/fármaco original de las ABC.
    E.5.1.1Timepoint(s) of evaluation of this end point
    PK:
    - 0.25 to 1 hour postdose (1 sample)
    - 1.5 to 3 hours postdose (1 sample)
    - 3.5 to 6 hours postdose (1 sample)
    - 6.5 to 8 hours postdose (1 sample)
    - 8.5 to 14 hours postdose (1 sample)
    - 24 to 36 hours postdose (1 sample)
    - 48 to 54 hours postdose (1 sample)
    For subsequent age cohorts, emerging PK concentration-time data from completing patients will be analyzed on an ongoing basis and used to refine and optimize the PK blood sampling scheme (i.e., both the number of samples and the sampling windows).
    FC:
    - De 0,25 a 1 hora después de la dosis (1 muestra)
    - De 1,50 a 3 horas después de la dosis (1 muestra)
    - De 3,50 a 6 horas después de la dosis (1 muestra)
    - De 6,50 a 8 horas después de la dosis (1 muestra)
    - De 8,50 a 14 horas después de la dosis (1 muestra)
    - De 24 a 36 horas después de la dosis (1 muestra)
    - De 48 a 54 horas después de la dosis (1 muestra)
    En el caso de las cohortes etarias posteriores, los datos FC resultantes de la relación concentración/tiempo de los pacientes que hayan finalizado el estudio se analizarán periódicamente y se emplearán para definir y optimizar el programa de extracción de las muestras de sangre para los análisis de FC (es decir, tanto el número de muestras como los márgenes del muestreo).
    E.5.2Secondary end point(s)
    - The PD endpoints will include observed, change-from-baseline, and percent-change-from-baseline PT, aPTT, and anti-FXa.
    - Safety assessments will include: AEs, physical examination findings, vital signs, standard hematology, clinical chemistry, coagulation, and urinalysis laboratory tests. Note, urinalysis will be performed with plastic bags with a sticky strip from neonates and infants with diapers.
    - Palatability of the liquid formulation will be assessed using visual analog scale (VAS) scores.
    Los criterios de valoración de FD incluirán la variación observada respecto al momento basal y la variación porcentual desde el momento basal del TP, el TTPa y los anti-FXa.
    - Las evaluaciones de la seguridad incluirán: AA, los hallazgos de la exploración física, las constantes vitales, el hemograma normalizado, la bioquímica clínica, la coagulación y las pruebas analíticas de orina. Debe tenerse en cuenta que en el caso de los neonatos y los lactantes que usen pañal, el análisis de orina se realizará con bolsas de plástico con tira adhesiva.
    - La agradabilidad de la fórmula farmacéutica líquida se evaluará mediante puntuaciones de una escala analógica visual (EAV).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Coagulation:
    - Predose (1 sample)
    - 0.25 to 1 hour postdose (1 sample)
    - 1.5 to 3 hours postdose (1 sample)
    - 3.5 to 6 hours postdose (1 sample)
    - 6.5 to 8 hours postdose (1 sample)
    - 24 to 36 hours postdose (1 sample)
    All other secondary endpoints - throughout the study
    Coagulación:
    - Antes de la administración de la dosis (1 muestra)
    - De 0,25 a 1 hora después de la dosis (1 muestra)
    - De 1,50 a 3 horas después de la dosis (1 muestra)
    - De 3,50 a 6 horas después de la dosis (1 muestra)
    - De 6,50 a 8 horas después de la dosis (1 muestra)
    - De 24 a 36 horas después de la dosis (1 muestra)
    Todos los demás criterios de valoración secundarios: hasta el final del estudio.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    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
    Metabolite exposure, palatability
    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
    PK, PD safety study
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Single-dose
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    France
    Italy
    Jordan
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    Ultima visita del ultimo paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months8
    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 Yes
    F.1.1Number of subjects for this age range: 48
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 12
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 24
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 12
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children <7 will be enrolled solely via parental consent. Children 7 - 17 will be enrolled via assent and parental consent.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 48
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients will continue normal treatment.
    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 Decision2016-06-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-23
    P. End of Trial
    P.End of Trial StatusOngoing
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