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    Summary
    EudraCT Number:2014-003952-29
    Sponsor's Protocol Code Number:BAY63-2521/15681
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-02-17
    Trial results View 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 number2014-003952-29
    A.3Full title of the trial
    Open-label, individual dose titration study to evaluate safety, tolerability and pharmacokinetics of riociguat in children from 6 to less than 18 years of age with pulmonary arterial hypertension (PAH)
    Estudio abierto con ajuste individualizado de la dosis, para evaluar la seguridad, la tolerabilidad y la farmacocinética de riociguat en niños de entre 6 y menos de 18 años de edad con hipertensión arterial pulmonar (HAP)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Riociguat for treatment of PAH in children from 6 to less than 18 years old
    Riociguat para el tratamiento de la HAP en niños de entre 6 y menos de 18 años de edad
    A.3.2Name or abbreviated title of the trial where available
    PATENT-CHILD
    PATENT-CHILD
    A.4.1Sponsor's protocol code numberBAY63-2521/15681
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/036/2015
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBayer Healthcare AG
    B.1.3.4CountryGermany
    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 supportBayer Healthcare AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer HealthCare AG
    B.5.2Functional name of contact pointClinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressCTP team/ Ref: "EU CTR"/ Bayer Pharma AG
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.4Telephone number0034.900102372
    B.5.6E-mailclinical-trialscontact@bayerhealthcare.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 Adempas
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Pharma AG
    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/3/07/518
    D.3 Description of the IMP
    D.3.1Product nameAdempas 0.5 mg
    D.3.2Product code BAY63-2521
    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 INNRiociguat
    D.3.9.1CAS number 625115-55-1
    D.3.9.2Current sponsor codeBAY63-2521
    D.3.9.3Other descriptive nameRIOCIGUAT
    D.3.9.4EV Substance CodeSUB32880
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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 Adempas
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Pharma AG
    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/3/07/518
    D.3 Description of the IMP
    D.3.1Product nameAdempas 1.0 mg
    D.3.2Product code BAY63-2521
    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 INNRiociguat
    D.3.9.1CAS number 625115-55-1
    D.3.9.2Current sponsor codeBAY63-2521
    D.3.9.3Other descriptive nameRIOCIGUAT
    D.3.9.4EV Substance CodeSUB32880
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.0
    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 Adempas
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Pharma AG
    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/3/07/518
    D.3 Description of the IMP
    D.3.1Product nameAdempas 1.5 mg
    D.3.2Product code BAY63-2521
    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 INNRiociguat
    D.3.9.1CAS number 625115-55-1
    D.3.9.2Current sponsor codeBAY 63-2521
    D.3.9.3Other descriptive nameRIOCIGUAT
    D.3.9.4EV Substance CodeSUB32880
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.5
    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 Yes
    D.2.1.1.1Trade name Adempas
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Pharma AG
    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/3/07/518
    D.3 Description of the IMP
    D.3.1Product nameAdempas 2.0 mg
    D.3.2Product code BAY63-2521
    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 INNRiociguat
    D.3.9.1CAS number 625115-55-1
    D.3.9.2Current sponsor codeBAY63-2521
    D.3.9.3Other descriptive nameRIOCIGUAT
    D.3.9.4EV Substance CodeSUB32880
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.0
    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 Yes
    D.2.1.1.1Trade name Adempas
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Pharma AG
    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/3/07/518
    D.3 Description of the IMP
    D.3.1Product nameAdempas 2.5 mg
    D.3.2Product code BAY63-2521
    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 INNRiociguat
    D.3.9.1CAS number 625115-55-1
    D.3.9.2Current sponsor codeBAY63-2521
    D.3.9.3Other descriptive nameRIOCIGUAT
    D.3.9.4EV Substance CodeSUB32880
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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 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/3/07/518
    D.3 Description of the IMP
    D.3.1Product nameRiociguat granules 0.3% for oral application
    D.3.2Product code BAY63-2521
    D.3.4Pharmaceutical form Granules for oral solution
    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 INNRiociguat
    D.3.9.1CAS number 625115-55-1
    D.3.9.2Current sponsor codeBAY63-2521
    D.3.9.3Other descriptive nameRIOCIGUAT
    D.3.9.4EV Substance CodeSUB32880
    D.3.10 Strength
    D.3.10.1Concentration unit % (W/W) percent weight/weight
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.3
    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 Yes
    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
    Pulmonary arterial hypertension (PAH)
    Hipertensión arterial pulmonar (HAP)
    E.1.1.1Medical condition in easily understood language
    Pulmonary arterial hypertension (PAH)
    Hipertensión arterial pulmonar (HAP)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10064911
    E.1.2Term Pulmonary arterial hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    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 is to evaluate safety, tolerability and pharmacokinetics of bodyweight adjusted riociguat treatment in children with PAH.
    El objetivo principal es evaluar la seguridad, la tolerabilidad y la farmacocinética del tratamiento con riociguat ajustado según el peso corporal en niños con HAP.
    E.2.2Secondary objectives of the trial
    Secondary exploratory objectives are to characterize the pharmacodynamic profile of riociguat comprising the following exploratory parameters: time to clinical worsening (TTCW), exercise capacity (6MWD test), functional capacity (measured by WHO FC), laboratory biomarkers (NT-proBNP), QoL measurements (SF-10), echocardiographic variables and taste assessment (questionnaire).
    Los objetivos exploratorios secundarios tienen como finalidad caracterizar el perfil farmacodinámico de riociguat y comprenden los siguientes parámetros exploratarios: tiempo hasta el empeoramiento clínico (THEC), capacidad de ejercicio (prueba 6MWD), capacidad funcional (medida por la CF de la OMS), biomarcadores de laboratorio (NT-proBNP), mediciones de la CdV (SF-10), parámetros ecocardiográficos y evaluación del sabor (cuestionario).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Children aged >=6 to <18 years.
    2. Diagnosed with PAH :
    - Idiopathic (IPAH)
    - Hereditable (HPAH)
    - PAH associated with (APAH)
    o Connective tissue disease
    o Congenital heart disease with shunt closure more than 6 months ago (no open shunts, confirmed by RHC no less than 4 months after surgery)
    3. Diagnosis of PAH confirmed by right heart catheterization (RHC) at any time prior to enrolment (for patients with closed shunts - RHC no less than 4 months after surgery)
    4. Pulmonary arterial hypertension confirmed by a RHC at any time prior to start of study, with mean pulmonary artery pressure (PAPmean) >=25 mmHg at rest, pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) <=15 mmHg, and pulmonary vascular resistance (PVR) >240 dyn.sec.cm-5 (i.e., >=3.0 wood units.m2)
    5. Patients must be treated with standard of care comprising background therapy and stable
    dose of bosentan (at least 12 weeks with stable doses).
    Two groups of patients will be included:
    o Prevalent: Patients currently on monotherapy with bosentan who need additional treatment (discretion of the investigator)
    o Incident: Treatment naïve patients initiated on bosentan then riociguat added once bosentan dose is stable for at least 12 weeks.
    6. WHO functional class I, II and III
    7. Adolescent females of childbearing potential can only be included in the study if a pregnancy test is negative. Adolescent females of childbearing potential must agree to use adequate contraception when sexually active. Adequate contraception is defined as any
    combination of at least 2 effective methods of birth control, of which at least one is a physical barrier (e.g. condoms with hormonal contraception or implants or combined oral contraceptives, certain intrauterine devices). Adequate contraception is required from the signing of the informed consent form up until 6 weeks after the last study drug administration.
    8. Young men must agree to use adequate contraception when sexually active.
    9. Written inform consent provided and if applicable child assent provided
    1. Niños de >= 6 a < 18 años
    2. Diagnosticados de HAP:
    -Idiopática (HAPI)
    -Hereditaria (HAPH)
    -HAP asociada a (HAPA)
    o Enfermedad del tejido conjuntivo
    o Cardiopatía congénita con cierre de derivación hace más de 6 meses (no hay derivaciones abiertas, confirmado mediante CCD 4 meses como mínimo después de la cirugía)
    3. Diagnóstico de HAP confirmada mediante cateterismo de las cavidades derechas (CCD) en cualquier momento antes de la inclusión (pacientes con derivaciones cerradas, CCD 4 meses como mínimo después de la cirugía)
    4. Hipertensión arterial pulmonar confirmada por una CCD en cualquier momento antes de comenzar el estudio, con una presión media en arteria pulmonar (PAPmedia) >=25 mm Hg en reposo, presión de enclavamiento en el capilar pulmonar (PECP) o presión telediastólica ventricular izquierda (PTDVI) <=15 mm Hg y resistencia vascular pulmonar (RVP) > 240 din.s.cm-5 (es decir, >=3,0 unidades Wood .m2)
    5. Los pacientes tienen que estar recibiendo tratamiento con el tratamiento de referencia, consistente en el tratamiento de base y una dosis estable de bosentán (al menos 12 semanas con dosis estables)
    Se incluirán dos grupos de pacientes:
    o Prevalentes: pacientes que reciben actualmente bosentán en monoterapia, que necesitan tratamiento adicional (a criterio del investigador)
    o Incidentes: pacientes que no han recibido tratamiento con anterioridad, en los que se inicia la administración de bosentán. Se añadirá el riociguat cuando la dosis de bosentán se mantenga estable durante al menos 12 semanas.
    6. Clase funcional I, II y III de la OMS
    7. Las mujeres adolescentes con capacidad de procrear solo pueden ser incluidas en el estudio si la prueba de embarazo es negativa. Las mujeres adolescentes con capacidad de procrear deberán aceptar el uso de un método anticonceptivo cuando sean sexualmente activas. Un método «anticonceptivo adecuado» se define como cualquier combinación de al menos 2 métodos anticonceptivos eficaces, de los cuales al menos uno es una barrera física (como preservativos con anticoncepción hormonal o implantes o anticonceptivos orales, determinados dispositivos intrauterinos). La anticoncepción adecuada es necesaria desde la firma del formulario de consentimiento informado hasta 6 semanas después de la última administración del fármaco del estudio
    8. Los varones jóvenes tienen que aceptar usar un método anticonceptivo adecuado cuando sean sexualmente activos
    9. Firma del consentimiento informado por escrito que se proporciona y, si procede, asentimiento pertinente del niño
    E.4Principal exclusion criteria
    1. Concomitant use of the following medications: phosphodiesterase (PDE) 5 Inhibitors (such as sildenafil, tadalafil, vardenafil) and non-specific PDE Inhibitors (theophylline, dipyridamole) in any form or pretreatment are not allowed.
    Concomitant use of nitrates or NO donors are allowed up to two weeks before Visit 1.
    2. Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization or any history of bronchial artery embolization or massive hemoptysis within 3 months prior to screening
    3. Systolic blood pressure (SBP) more than 5 mmHg lower than the age-, sex- and height-adapted level of the 50th SBP percentile (NHBPEP, 2004)
    4. History of left-sided heart disease, including valvular disease or heart failure
    5. Pulmonary hypertension related to conditions other than specified in the inclusion criteria
    6. WHO functional class IV
    7. Pulmonary veno-occlusive disease
    8. Screening aspartate transaminase (AST) and/ or alanine transaminase (ALT) more than 3 times the upper limit of normal (ULN)
    9. Non-stable disease status, e.g. , signs and symptoms of decompensated right heart failure
    10. Severe bronchial asthma
    11. Severe restrictive lung disease
    12. Severe congenital abnormalities of the lung, thorax, and diaphragm
    13. Clinically relevant hepatic dysfunction (especially Child Pugh C)
    14. Renal insufficiency (estimated glomerular filtration rate <30 mL/min/1.73m2 e.g. calculated based on Schwartz formula)
    15. Subject with hypersensitivity to the investigational drug or any of the excipients
    16. Active smoking of tobacco of any type or quantity
    17. Subjects with known HIV infection (evaluated by medical history)
    18. Previous assignment to treatment during this study
    19. Previous (within 30 days) or concomitant participation in another clinical study with investigational medicinal product(s)
    20. Any condition that, according to treating physician, might jeopardize subject's participation and compliance with procedures indicated in this protocol.
    1. Uso concomitante de los medicamentos siguientes: no se permiten inhibidores de la fosfodiesterasa 5 (como sildenafilo, tadalafilo y vardenafilo) e inhibidores inespecíficos de la fosfodiesterasa (PDE) (teofilina y dipiridamol) en cualquier forma o tratamiento previo. Se permite el uso concomitante de nitratos o donantes de NO hasta dos semanas antes de la visita 1.
    2. Estado activo de hemoptisis o hemorragia pulmonar, incluidos los acontecimientos tratados mediante embolización de una arteria bronquial o antecedentes de embolización de una arteria bronquial o hemoptisis masiva en los 3 meses anteriores a la selección
    3. Presión arterial sistólica (PAS) más de 5 mm Hg menor que el nivel adaptado del percentil 50 de la PAS adaptada según la edad, el sexo y la estatura (NHBPEP, 2004)
    4. Antecedentes de enfermedad cardíaca izquierda, incluida la enfermedad valvular o la insuficiencia cardíaca
    5. Hipertensión pulmonar relacionada con afecciones distintas de las que se especifican en los criterios de inclusión
    6. Clase funcional IV de la OMS
    7. Enfermedad venosa oclusiva pulmonar
    8. Aspartato transaminasa (AST) y/o alanina transaminasa (ALT) más de 3 veces el límite superior de la normalidad (LSN)
    9. Enfermedad en estado inestable, por ejemplo, signos y síntomas de insuficiencia cardíaca derecha descompensada
    10. Asma bronquial grave
    11. Enfermedad pulmonar restrictiva grave
    12. Anomalías congénitas graves en pulmón, tórax y diafragma
    13. Disfunción hepática de importancia clínica (especialmente, clase C de ChildPugh)
    14. Insuficiencia renal (filtración glomerular estimada < 30 ml/min/1,73m2, p. ej., calculada según la fórmula de Schwartz)
    15. Paciente con hipersensibilidad al fármaco en investigación o a cualquiera de los excipientes
    16. Tabaquismo activo de cualquier tipo o cantidad
    17. Pacientes con infección por VIH diagnosticada (evaluada mediante los antecedentes médicos)
    18. Asignación previa a un tratamiento durante este estudio
    19. Participación previa (en los 30 días anteriores) o simultánea en otro estudio clínico con medicamentos en investigación
    20. Cualquier afección que, en opinión del médico responsable del tratamiento, pudiera poner en peligro la participación del paciente y el cumplimiento de los procedimientos indicados en este protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    - Incidence of adverse events and serious adverse events
    - Recording of vital signs
    - Left-hand x-ray
    - Pharmacokinetics/Pharmacodynamics analyses
    - Incidencia de acontecimientos adversos y acontecimientos adversos graves
    - Registro de constantes vitales
    - Radiografía de la mano izquierda
    - Análisis farmacocinético/farmacodinámico
    E.5.1.1Timepoint(s) of evaluation of this end point
    Assessment of Adverse Events at baseline, at all visits in the titration phase and maintenance phase, and every 3-4 months in the extension phase.
    Left hand x-ray at baseline, end of study treatment period (week 24) and every 12 months in the extension phase until growth plates are closed.
    Evaluación de acontecimientos adversos en el momento inicial, en todas las visitas de la fase de ajuste de la dosis y de la fase de mantenimiento y cada 3-4 meses en la fase de extensión.
    Radiografía de la mano izquierda en el momento inicial, al final del período de tratamiento del estudio semana 24) y cada 12 meses en la fase de extensión hasta que se cierren las placas de crecimiento.
    E.5.2Secondary end point(s)
    - 6-Minute Walking Distance (6MWD).
    - WHO functional class.
    - N-terminal prohormone brain-type natriuretic peptide.
    - Quality of Life scores (parent questionnaire and in children able to understand questions).
    - Echocardiographic parameters including:
    o pulmonary arterial systolic pressure (PASP),
    o tricuspid annular plane systolic excursion (TAPSE),
    o pericardial effusion,
    o left ventricular eccentricity index,
    o estimated inferior vena cava pressure.
    - Time to clinical worsening defined as:
    o hospitalization for right heart failure,
    o death,
    o lung transplantation,
    o Pott?s anastomosis and atrioseptostomy
    o worsening of PAH symptoms, which must include either an increase in WHO functional class, OR both appearance/worsening symptoms of right heart failure AND need for additional PAH therapy.
    -Taste and texture of the pediatric formulation(s) must be assessed by use of a questionnaire.
    - Distancia caminada en 6 minutos (6MWD).
    - Clase funcional de la OMS.
    - Prohormona aminoterminal del péptido natriurético cerebral.
    - Puntuaciones de calidad de vida (cuestionario para padres y para niños capaces de entender las preguntas).
    - Parámetros del ecocardiograma, incluidos:
    o presión sistólica en la arteria pulmonar (PASAP),
    o desplazamiento sistólico en el plano anular tricuspídeo (DSPAT),
    o derrame pericárdico,
    o índice de excentricidad del ventrículo izquierdo,
    o presión estimada en la vena cava inferior.
    - Tiempo hasta el empeoramiento clínico, definido como
    o hospitalización por insuficiencia cardíaca derecha,
    o muerte,
    o trasplante de pulmón,
    o anastomosis de Pott y auriculoseptostomía,
    o empeoramiento de los síntomas de HAP, que tiene que incluir un aumento de la clase funcional de la OMS
    O la aparición o empeoramiento de síntomas de insuficiencia cardiaca derecha Y necesidad de tratamiento adicional para la HAP.
    - El sabor y la textura de las formulaciones pediátricas tienen que evaluarse mediante un cuestionario.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Changes from baseline to end of treatment (week 24)
    Variación con respecto al valor inicial al final del tratamiento (semana 24)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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 No
    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.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    France
    Germany
    Hungary
    Italy
    Japan
    Netherlands
    Poland
    Spain
    Turkey
    United Kingdom
    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
    In accordance to the EU guideline 2009/c28/01 the end of the study will be reached as soon as the last visit of the last subject has been reached in all centers in all participating countries (EU and non-EU) after 24 weeks of treatment.
    The LTE is not considered part of the main study and the results will be reported separately.
    De acuerdo con la norma de la UE 2009/c28/01, el final del estudio será en cuanto se haya alcanzado la última visita del último paciente en todos los centros en todos los países participantes (UE y otros) después de 24 semanas de tratamiento.
    La ELP no se considera parte del estudio principal y los resultados se publicarán por separado.
    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 months3
    E.8.9.1In the Member State concerned days11
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days11
    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: 20
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 10
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    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 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 state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 15
    F.4.2.2In the whole clinical trial 20
    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 require treatment with riociguat for more than 24 weeks will be offered participation in an optional extension phase.
    Subjects will receive riociguat until they can be transitioned to approved Adempas.
    Se ofrecerá a los pacientes que necesiten tratamiento con riociguat durante más de 24 semanas la posibilidad de participar en una fase de extensión opcional.
    Los pacientes recibirán riociguat hasta que puedan cambiar al medicamento aprobado Adempas.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation UK NIHR CRN, Coordinating Centre
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-04-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-31
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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