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    Summary
    EudraCT Number:2016-001067-36
    Sponsor's Protocol Code Number:18588
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-09-09
    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 number2016-001067-36
    A.3Full title of the trial
    A prospective, randomized, international, multicenter, double-arm, controlled, open-label study of Riociguat in patients with pulmonary arterial hypertension (PAH) who are on a stable dose of phosphodiesterase-5 inhibitors (PDE-5i) with or without endothelin receptor antagonist (ERA), but not at treatment goal
    Un estudio abierto, prospectivo, aleatorizado, internacional, multicéntrico, con dos grupos y controlado con riociguat en pacientes afectados por hipertensión arterial pulmonar (HAP) que están siendo tratados con una dosis estable de inhibidores de la fosfodiesterasa 5 (PDE-5i) combinados o no con antagonistas de los receptores de la endotelina (ERA) pero no han alcanzado el objetivo del tratamiento.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to find out whether some PAH patients may benefit by replacing their current phosphodiesterase-5 inhibitors (PDE-5i) with or without endothelin receptor antagonist (ERA), with Riociguat
    Un estudio para averiguar si algunos pacientes con HAP pueden beneficiarse mediante la sustitución de sus actuales inhibidores de la fosfodiesterasa-5 (PDE-5i) con o sin antagonista del receptor de endotelina (ERA), con Riociguat
    A.3.2Name or abbreviated title of the trial where available
    Riociguat rEplacing PDE-5i therapy evaLuated Against Continued PDE-5i thErapy
    Tratamiento de sustitución de PDE-5i por riociguat evaluado frente al tratamiento continuado con PDE
    A.4.1Sponsor's protocol code number18588
    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 SponsorBayer 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 AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressN/A
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.4Telephone number0034900102372
    B.5.6E-mailclinical-trials-contact@bayer.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 film-coated tablets
    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 film-coated tablets
    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 film-coated tablets
    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 number1.5
    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 film-coated tablets
    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 film-coated tablets
    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 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 Adcirca
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V.
    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 nameADCIRCA 20 mg film-coated tablets
    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 INNTADALAFIL
    D.3.9.1CAS number 171596-29-5
    D.3.9.4EV Substance CodeSUB12602MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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: 7
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Revatio
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    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 nameRevatio 20 mg film-coated tablets
    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 INNSILDENAFIL CITRATE
    D.3.9.1CAS number 171599-83-0
    D.3.9.4EV Substance CodeSUB04386MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    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 19.0
    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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the proportion of patients in each treatment arm with a satisfactory clinical response as defined by a composite primary endpoint at Week 24.
    El objetivo principal es evaluar la proporción de pacientes de cada grupo de tratamiento que obtiene una respuesta clínica satisfactoria según lo definido por un criterio principal de valoración compuesto en la Semana 24.
    E.2.2Secondary objectives of the trial
    To demonstrate safety and clinical effect at Week 24 indicated by change in 6-minute walking distance (6MWD), N-terminal pro-brain natriuretic peptide (NT-proBNP), World Health Organization Functional Class (WHO FC) and clinical worsening from baseline in each treatment arm.
    Demostrar los efectos clínicos y sobre la seguridad en la Semana 24, indicados mediante un cambio en la distancia cubierta durante la prueba de seis minutos de marcha (6MWD), el fragmento N-terminal del propéptido natriurético cerebral (NT-proBNP), la clase funcional según la Organización Mundial de la Salud (CF OMS) y el empeoramiento clínico del estado inicial en cada grupo de tratamiento.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male and female patients aged 18 to 75 years.
    2. Patients with symptomatic PAH with a pulmonary vascular resistance (PVR) > 400 dyn*sec*cm-5, mean pulmonary artery pressure ≥ 25 mmHg, and pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg as assessed by the most recent right heart catheterization (RHC) within 12 months prior to screening. Alternatively, PCWP
    can be replaced by left ventricular end-diastolic pressure (≤ 15 mmHg).
    PAH of the following types:
    a. Idiopathic
    b. Hereditary
    c. Drug and toxin induced PAH
    d. Associated with PAH due to:
    - Connective tissue disease (CTD)
    - Congenital heart disease, but only if the patient underwent surgical
    repair more than one year before enrolment
    - Portal hypertension with liver cirrhosis (Note: patients with clinical
    relevant hepatic dysfunction are excluded; see exclusions related to
    disorders in organ function)
    3. Patients who are on stable doses of a PDE-5i and ERA combination therapy or on stable PDE-5i monotherapy 6 weeks prior to and at randomization but not at treatment goal (tadalafil 20 to 40 mg once daily or sildenafil at least 60 mg daily dose).
    4. WHO FC III at screening and at randomization.
    5. 6MWD test between 165 m and 440 m at screening and at randomization.
    6. Stable dose of diuretics, if used, for at least 30 days prior to and at randomization.
    7. Patients who are able to understand and follow instructions and who are able to participate in the study for the entire study.
    8. Patients must have given their written informed consent to participate in the study after having received adequate previous information and prior to any study-specific procedures.
    1. Pacientes adultos (entre 18 y 75 años)
    2. Los pacientes con HAP sintomática con una resistencia vascular pulmonar (RVP) > 400 dyn*s*cm-5, una presión arterial pulmonar media ≥ 25 mm Hg y una presión capilar pulmonar en cuña (PCPC) ≤ 15 mm Hg evaluadas por cateterismo cardíaco derecho en los 12 meses anteriores a la fase de selección. Como alternativa, la PCPC puede sustituirse por la presión diastólica final del ventrículo izquierdo.
    HAP de los siguientes tipos:
    a. idiopática
    b. hereditaria
    c. inducida por fármacos o toxinas
    d. HAP asociada a:
    - enfermedad del tejido conectivo
    - enfermedad cardíaca congénita (los pacientes se han tenido que someter a reparación quirúrgica más de 1 año antes de la incorporación al estudio)
    - hipertensión portal con cirrosis hepática (se excluye a los pacientes con disfunción hepática clínicamente relevante).
    3. Los pacientes a los que se administren dosis estables de un tratamiento combinado de PDE-5i y ERA o una monoterapia estable de PDE-5i durante, al menos, 6 semanas antes de la aleatorización y en el momento de producirse esta (dosis diarias de entre 20 y 40 mg de tadalafilo o dosis diarias de 60 mg, al menos, de sildenafilo).
    4. OMS FC III en la selección y en la aleatorización.
    5. Resultados en la 6MWD de 165-440 m en las fases de selección y aleatorización.
    6. Dosis estable de diuréticos, si se utiliza, por lo menos 30 días antes y en la aleatorización.
    7. Pacientes que son capaces de entender y seguir instrucciones y que son capaces de participar en el estudio durante todo el estudio.
    8. Pacientes que hayan firmado el consentimiento informado y sean capaces de seguir las instrucciones del estudio.
    E.4Principal exclusion criteria
    1. Participation in another interventional clinical study within 30 days prior to screening.
    2. Previous randomization to treatment during this study (no re-randomization).
    3. Previous treatment with riociguat.
    4. Pregnant women, or breast feeding women, or women with childbearing potential not using a combination of safe contraception methods.
    5. Patients with a medical disorder, condition, or history of such that would impair the patient’s ability to participate or complete this study, in the opinion of the investigator.
    6. Patients with substance abuse (e.g.,alcohol or drug abuse) within the previous 3 months prior to and at randomization.
    7. Patients with underlying medical disorders with an anticipated life expectancy below 2 years (e.g.,active cancer disease with localized and/or metastasized tumor mass).
    8. Patients with a history of severe allergies or multiple drug allergies.
    9. Patients with hypersensitivity to the investigational drug or any of the excipients.
    10. Patients unable to perform a valid 6MWD test (e.g.,orthopedic disease, peripheral artery occlusive disease, which affects the patient’s ability to walk).
    11. Participation at a supportive physical training program, defined as a structured exercise and rehabilitation program supervised by a physician and/or a physiotherapist is not allowed during the pretreatment and the treatment phase of the study (up to the EOS visit).
    12. Excluded medication/treatment:
    a. Patients who are screened for possible participation in the study must not be withdrawn from treatments which are medically required. If such treatments are not in-line with the entry criteria of this study, the patient must not be enrolled. Concomitant use with riociguat of the following specific medications for treatment of PAH is not allowed at any time during the study:
    • PDE-5i must not be co-administered with riociguat
    • Non-specific PDE-inhibitors
    • NO donors
    b. Prostacyclin analogues (PCA) and prostacyclin-receptor agonists (PRA) by any administration route within 30 days prior to and at randomization (except for vasoreactivity testing).
    13. Exclusion criteria related to pulmonary disease:
    a. All types of PH except subtypes of Dana Point Group I specified in the inclusion criteria.
    b. Evidence of clinically significant restrictive or obstructive parenchymal lung diseases in the judgment of the investigator
    c. Severe congenital abnormalities of the lungs, thorax, and diaphragm.
    d. Severe restrictive lung disease (total lung capacity [TLC] < 60%).
    e. Moderate obstructive lung disease (forced expiratory volume in one second/forced vital capacity [FEV1/FVC] < 50%).
    f. Confirmed obstructive sleep apnea
    g. Severe diffusion impairment (diffusing capacity of the lung for carbon monoxide < 30% predicted).
    h. History or active state of serious hemoptysis/pulmonary hemorrhage including those managed by bronchial artery embolization
    14. Exclusion criterion related to hypoxia (pulse oximeter at rest):
    a. Peripheral capillary oxygen saturation (SpO2) < 88% despite supplemental oxygen therapy (< 4 L/min) at rest.
    15. Cardiovascular exclusion criteria:
    a. Uncontrolled arterial hypertension (SBP > 180 mmHg and/or diastolic BP > 110 mmHg).
    b. SBP < 95 mmHg prior to and at randomization.
    c. Resting heart rate in the awake patient < 50 bpm or > 105 bpm.
    d. Permanent atrial fibrillation and new onset of atrial fibrillation within the last 3 months prior to screening.
    e. Left ventricular systolic dysfunction by echocardiography (left ventricular ejection fraction [LVEF] < 40%, Simpson’s methodology).
    f. Hypertrophic obstructive cardiomyopathy.
    g. Severe proven or suspected coronary artery disease (patients with Canadian Cardiovascular Society Angina Classification class 2 to 4, and/or requiring nitrates, and/or acute coronary syndrome, or coronary interventions (PCI,CABG) within the last 3 months prior to and at randomization).
    h. Clinical evidence of symptomatic atherosclerotic disease (e.g., peripheral artery disease with reduced walking distance, history of stroke with persistent neurological deficit etc.).
    i. History of stroke within 3 months prior to and at randomization.
    j. Congenital or acquired valvular or myocardial disease if clinically significant apart from tricuspid valvular insufficiency due to PAH.
    k.Three or more of the following left ventricular disease/ dysfunction risk factors:
    • Body Mass Index (BMI) ≥ 30
    • History of Essential Hypertension
    • Diabetes mellitus of any type
    • History of significant Coronary Disease
    16. Exclusion criteria related to disorders in organ function:
    a. Clinical relevant hepatic dysfunction indicated by:
    • Bilirubin > 2 times upper limit of normal (ULN), and/or
    • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times ULN
    b. Signs of severe hepatic insufficiency, and/or
    c. Renal insufficiency
    17. Other exclusion criteria:
    a. Other co-morbidities impairing exercise capacity
    1. Participación en otro estudio clínico de intervención dentro de los 30 días anteriores a la selección.
    2. Aleatorización previa al tratamiento durante este estudio (sin re-aleatorización).
    3. Tratamiento previo con riociguat.
    4. Las mujeres embarazadas o en periodo de lactancia, o en edad fértil que no usen una combinación de métodos anticonceptivos seguros.
    5. Los pacientes con un trastorno médico, condición, o la historia de tal manera que puedan menoscabar la capacidad del paciente para participar o completar este estudio, en opinión del investigador.
    6. Los pacientes con abuso de sustancias (por ejemplo, alcohol o abuso de drogas) en los 3 meses anteriores previos y en la aleatorización.
    7. Los pacientes con trastornos médicos subyacentes con una esperanza de vida previsto por debajo de 2 años.
    8. Los pacientes con antecedentes de alergias graves o múltiples alergias a medicamentos.
    9. Los pacientes con hipersensibilidad al fármaco en investigación o cualquiera de los excipientes.
    10. Los pacientes incapaces de realizar una prueba de 6MWD válida.
    11. Participación en un programa de entrenamiento físico de apoyo, que se define como un programa de ejercicio y rehabilitación estructurada bajo la supervisión de un médico y / o un fisioterapeuta no está permitido durante el tratamiento previo y la fase de tratamiento del estudio (hasta la visita EOS).
    12. Medicación / tratamiento excluidos:
    a. Los pacientes que son examinados para detectar la posible participación en el estudio no deben ser retirados de los tratamientos que son necesarios por razones médicas. Si estos tratamientos no están en línea con los criterios de ingreso de este estudio, el paciente no debe estar inscrito. El uso concomitante con riociguat de los siguientes medicamentos específicos para el tratamiento de la HAP no se permite en cualquier momento durante el estudio:
    • PDE-5i no debe ser co-administrado con riociguat
    • PDE-inhibidores no específicos
    • donadores de NO
    segundo. análogos de la prostaciclina (PCA) y los agonistas del receptor de prostaciclina (PRA) por cualquier vía de administración dentro de los 30 días anteriores a la aleatorización y en (a excepción de las pruebas de reactividad vascular).
    13. Los criterios de exclusión relacionadas con la enfermedad pulmonar:
    a. Todos los tipos de PH excepto subtipos de Dana Point Grupo I especificados en los criterios de inclusión.
    b. Evidencia de enfermedades del parénquima pulmonar restrictiva u obstructiva clínicamente significativas en el criterio del investigador
    c. Anomalías congénitas graves de los pulmones, el tórax y el diafragma.
    d. Enfermedad pulmonar restrictiva grave (capacidad pulmonar total [TLC] <60%).
    e. Enfermedad pulmonar obstructiva moderada.
    f. Confirmada apnea obstructiva del sueño.
    g. Difusión deterioro grave.
    h. Historia o estado activo de hemoptisis grave hemorragia/pulmonar incluyendo los gestionados por la embolización de arterias bronquiales
    14. Criterio de exclusión relacionada con la hipoxia
    a. la saturación capilar periférica de oxígeno (SpO2)<88% a pesar de la terapia de oxígeno suplementario (<4 L/min) en reposo.
    15. Criterios de exclusión cardiovasculares:
    a. Hipertensión arterial no controlada (PAS> 180 mmHg y/o diastólica> 110 mmHg).
    b. PAS <95 mmHg antes y en la aleatorización.
    c. Frecuencia cardíaca en reposo en el paciente despierto<50 latidos por minuto o>105 lpm.
    d. Fibrilación auricular permanente y la nueva aparición de la fibrilación auricular en los últimos 3 meses anteriores a la selección.
    e. La disfunción sistólica ventricular izquierda por ecocardiografía.
    f. Miocardiopatía hipertrófica obstructiva.
    g. Enfermedad de la arteria coronaria, o se sospeche severa (pacientes con clase Canadian Cardiovascular Sociedad de Clasificación Angina 2 a 4, y / o que requieren nitratos, y / o el síndrome coronario agudo, o intervenciones coronarias (PCI, CABG) en los últimos 3 meses antes y en aleatorización).
    h. Evidencia clínica de la enfermedad aterosclerótica sintomática (por ejemplo, enfermedad arterial periférica con una menor distancia a pie, antecedentes de accidente cerebrovascular con déficit neurológico persistente etc.).
    i. Antecedentes de accidente cerebrovascular dentro de los 3 meses anteriores a la aleatorización y en.
    j. valvular congénita o adquirida o enfermedad miocárdica si clínicamente significativo, aparte de insuficiencia valvular tricúspide debido a la HAP.
    k.Three o más de los siguientes factores de riesgo de enfermedad / disfunción ventricular izquierda:
    • Índice de Masa Corporal (IMC) ≥ 30
    • Historia de la hipertensión esencial
    • Diabetes mellitus de cualquier tipo
    • antecedentes de enfermedad coronaria significativa
    16. Los criterios de exclusión relacionados con los trastornos en la función del órgano:
    a. La disfunción hepática clínicamente relevante
    b. Insuficiencia renal
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint ‘satisfactory clinical response’ is defined as the composite endpoint comprising the following components (independent central adjudication):
    2 of 3 must be fulfilled
    - 6MWD increase by ≥ 10% or ≥ 30 m from baseline to Week 24
    - WHO FC I or II at Week 24
    - NT-proBNP reduction ≥ 30% from baseline to Week 24 (NT-proBNP ratio Week 24/baseline ≤ 0.7), AND
    - No clinical worsening (for definition, see protocol)
    El criterio principal de valoración de la eficacia, «respuesta clínica satisfactoria», se define como un criterio de valoración compuesto integrado por los siguientes componentes (adjudicación central independiente):
    Deben cumplirse 2 de los 3
    - Incremento ≥ 10 % o ≥ 30 m en la prueba 6MWD desde el inicio del estudio hasta la Semana 24
    - CF OMS I o II en la Semana 24
    -Reducción ≥ 30 % en el NT-proBNP desde el inicio del estudio hasta la Semana 24 (relación entre NT-proBNP en la Semana 24 e inicial ≤ 0,7), Y
    - Ausencia de empeoramiento clínico (para definición ver protocolo?
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 Weeks
    24 Semanas
    E.5.2Secondary end point(s)
    - Change from baseline in 6MWD (blinded assessment)
    - Change from baseline in NT-proBNP
    - Change from baseline in WHO FC (blinded assessment)
    - Clinical worsening
    - Cambio desde el inicio en 6MWD (evaluación cegada)
    - Cambio desde el inicio en el NT-proBNP
    - Cambio desde el inicio en la OMS FC (evaluación cegada)
    - Empeoramiento clínico
    E.5.2.1Timepoint(s) of evaluation of this end point
    24 Weeks
    24 Semanas
    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 No
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA54
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Brazil
    Canada
    Czech Republic
    Denmark
    France
    Germany
    Greece
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    New Zealand
    Portugal
    Spain
    Switzerland
    Taiwan
    Turkey
    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
    Última visita del último 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 months4
    E.8.9.1In the Member State concerned days14
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days5
    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: 164
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 54
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 218
    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)
    Standard of Care
    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 Decision2016-11-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-03-03
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