Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42585   clinical trials with a EudraCT protocol, of which   7011   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2010-018863-40
    Sponsor's Protocol Code Number:BAY63-2521/15096
    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:2011-06-20
    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 number2010-018863-40
    A.3Full title of the trial
    An interaction study to evaluate changes in blood pressure following 1, 1.5, 2, and 2.5 mg riociguat tid (dose titration) compared to placebo treatment on the background of stable sildenafil pretreatment in subjects with symptomatic pulmonary arterial hypertension
    Ensayo de interacción para evaluar los cambios producidos en la presión arterial sistémica tras la administración de 1 mg, 1,5 mg, 2 mg y 2,5 mg de riociguat tres veces al día (titulación de dosis) comparado con placebo, en pacientes con hipertensión arterial pulmonar sintomática y que se encuentran en tratamiento estable con sildenafilo.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of the pharmacodynamic effect of the combination of Sildenafil and Riociguat on blood pressure and other safety parameters
    Evaluación de los efectos farmacodinámicos de la combinación de sildenafilo y riociguat en la presión arterial y en otros parámetros de seguridad
    A.3.2Name or abbreviated title of the trial where available
    PATENT PLUS
    A.4.1Sponsor's protocol code numberBAY63-2521/15096
    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 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 Schering Pharma 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 pointCTP Team / Ref: "EU CTR" /
    B.5.3 Address:
    B.5.3.1Street AddressBayer Schering Pharma AG, S102, Level 2, Room 156
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.6E-mailclinical-trials-contact@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 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 nameBAY 63-2521 IR tablets 1.0 mg
    D.3.2Product code BAY 63-2521
    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 nameMethyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/07/518
    D.3 Description of the IMP
    D.3.1Product nameBAY 63-2521 IR tablets 1.5 mg
    D.3.2Product code BAY 63-2521
    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 nameMethyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo
    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: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/07/518
    D.3 Description of the IMP
    D.3.1Product nameBAY 63-2521 IR tablets 2.0 mg
    D.3.2Product code BAY 63-2521
    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 nameMethyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/07/518
    D.3 Description of the IMP
    D.3.1Product nameBAY 63-2521 IR tablets 2.5 mg
    D.3.2Product code BAY 63-2521
    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 nameMethyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo
    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: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/07/518
    D.3 Description of the IMP
    D.3.1Product nameBAY 63-2521 IR tablets 0.5 mg
    D.3.2Product code BAY 63-2521
    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 nameMethyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pulmonary arterial hypertension
    Hipertensión pulmonar
    E.1.1.1Medical condition in easily understood language
    Patients with clinical symptoms due abnormally high blood pressure in the lung blood vessels
    Pacientes con sintomatomatología clinica por hipertensión arterial pulmonar
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 13.1
    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
    To evaluate the effect of 1, 1.5, 2, and 2.5 mg riociguat tid (dose titration) administered simultaneously with sildenafil on blood pressure in subjects with symptomatic pulmonary arterial hypertension.
    Evaluar el efecto en la presión arterial sistémica de 1mg, 1,5 mg, 2 mg y 2,5 mg de riociguat tres veces al día (titulación de dosis) administrado simultaneamente con sildenafilo en pacientes con hipertensión arterial pulmonar sintomática.
    E.2.2Secondary objectives of the trial
    To investigate the safety of the riociguat/sildenafil combination and changes in 6-minute walk test, WHOf unctional class, N terminal pro-brain natriuretic peptide, and variables obtained during right-heart catheterization after 12 weeks of treatment; pharmacokinetics of riociguat and sildenafil.
    Evaluar la seguridad de la combinación riociguat/sildenafilo y los cambios en el test de 6 minutos, clase funcional de la OMS, fragmento N terminal del propétpido natriurético cerebral (NT-pro BNP), y las variables conseguidas durante el cateterismo cardíaco derecho después de 12 semanas de tratamiento; el perfil farmacocinético de riociguat y sildenafilo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ?18 to 75 years of age at Visit 1 (the lower age limit may be higher if legally requested in the participating countries).
    ?Male and female subjects with symptomatic PAH (Group I Dana Point Updated Clinical Classification 2008), a 6-min walking distance (6MWD) of more than 150 m, a pulmonary vascular resistance (PVR) >300 dyn*s*cm-5, and a mean pulmonary artery pressure (PAPmean) > 25 mmHg either due to:
    -Idiopathic PAH.
    -Heritable PAH.
    -Associated PAH due to connective tissue disease.
    -Associated PAH due to congenital heart disease (ie atrial septal defect, ventricle septal defect, persistent ductus arteriosus), if subjects underwent surgical correction >360 days before study inclusion.
    -Associated PAH due to portal hypertension with liver cirrhosis. (Note: subjects with clinical relevant hepatic dysfunction are excluded; see exclusions related to disorders in organ function.)
    -Associated PAH due to anorexigen or amphetamine use.
    Note: Other PAH subtypes of Dana Point Updated Clinical Classification Group I than the ones listed above, for example (eg) PAH associated with human immunodeficiency virus (HIV) infection, are excluded from the trial (see exclusion criteria).
    Note: With respect to the verification of the inclusion criteria, PAPmean and PVR are considered as calculated parameters.
    Note: Subjects who originally failed screening due to the upper limit of the 6MWD in the original study protocol can be re-screened.
    ?For Study Part 1: subjects on stable pretreatment with sildenafil at a dose of 20 mg tid.

    "Stable" is defined as no change in the respective daily dose for at least 90 days prior to randomization.

    ?For Study Part 2: subjects on stable pretreatment with sildenafil as prescribed by the treating physician (but not higher than 80 mg tid).

    "Stable" is defined as no change in the respective daily dose for at least 90 days prior to randomization.
    ?Unspecific treatments which may also be used for the treatment of PAH such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation are permitted. However, treatment with anticoagulants (if indicated) must have been started at least 30 days before Visit 1 and treatment with diuretics needs to be stable for at least 30 days before Visit 1.
    ?Subjects with supplemental long-term oxygen therapy may be included, if the amount of supplemental oxygen and the delivery method was stable on average for at least 90 days before Visit 1.
    ?SBP >/=95 mmHg and heart rate (HR) </=105 beats per minute (BPM) in the first 2 h after intake of sildenafil (measured at Visits 0 and 1).
    ?Women without child-bearing potential defined as postmenopausal women (ie permanent absence of monthly periods for more than 2 years), women with bilateral tubal ligation, women with bilateral ovarectomy, and women with hysterectomy can be included in the study. Women with childbearing potential may only be included in the study if a serological pregnancy test is negative and a combination of 2 effective methods of birth control (eg prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method, male partner sterilization) are used throughout the study.
    ?Subjects who are able to understand and follow instructions and who are able to participate in the study for the entire period.
    ?Subjects 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.
    ?18 a 75 años de edad en la Visita 1 (el limite de edad más bajo puede aumentar si es requerimiento en algún país participante).
    ?Pacientes varones y mujeres con HAP sintomática (Grupo 1 de la Clasificación Dana Point 2008), prueba de marcha de 6 minutos (6MWD) de más de 150 m, una resistencia vascular pulmonar (RVP) > 300 dyn*s*cm-5, y una presión arterial pulmonar (PAP media) > 25 mmHg bien debido a:
    -HAP idiopática
    -HAP familiar
    -HAP asociada a una enfermedad del tejido conectivo
    -HAP asocidada debida a enfermedad cardiaca congénita (es decir, defecto septal auricular, defecto septal ventricular, ducturs arteriosus persistente), si desde que los pacientes se sometieron a corrección quirúrgica han transcurido más de 360 días antes de la inclusión en el estudio.
    -HAP asociada debida a hipertensión portal con cirrosis hepática (Nota: los pacientes con alteraciones hepáticas clínicas relevantes están excluidos: ver exclusiones asociadas con alteraciones en la función de organos).
    -PAH asociada debida al uso de anorexígenos o anfetaminas.
    Nota: están excluídos del estudio otros subitpos del HAP Grupo I de la Clasificación de Dana Point 2008, diferentes a los listados arriba, por ejemplo, PAH asociada a la infección por el virus de inmunodeficiencia humana (VIH) (ver criterios de exclusión).
    Nota: Con respecto a la verificación de los criterios de inclusión se consideran a la PAPmedia y la RVP como parámetros calculados.
    Nota: Los pacientes que inicialmente fueron fallo de selección debido al limite superior del 6MWD en el protocolo original pueden ser seleccionados nuevamente.
    ?Para la parte I del Estudio: Los pacientes en pretratamiento estable con sildenafilo a dosis de 20 mg tres veces al día.
    "Estable" se define como ningún cambio en la respectiva dosis diaria durante al mentos 90 días antes de la aleatorización.
    ?Para la Parte II del Estudio: Los pacientes en pretatamiento estable con sildenafilo como le prescribio su médico (pero no dosis superiores a 80 mg tres veces al día).
    "Estable" se define como ningún cambio en la respectiva dosis diaria durante al mentos 90 días antes de la aleatorización.
    ?Están permitidos los tratamientos inespecíficos que también pueden utilizarse en el tratamiento de la hipertensión pulmonar tales como: anticoagulantes orales, diuréticos, digitálicos, bloqueantes de los canales de calcio o suplementadores de oxígeno. No obstante, el tratamiento con anticoagulantes (si está indicado) debe haberse iniciado al menos 30 días antes de la Visita 1 y el tratamiento con diuréticos debe haberse estabilizado al menos 30 días antes de la Visita 1.
    ?Los pacientes con tratamiento suplementario con oxígeno a largo plazo pueden incluirse, si la cantidad de aporte de oxígeno suplementario y el método de administración han sido estables durante al menos 90 días antes de la Visita 1.
    ?PAS>/= 95mmHg y frecuencia cardiaca (FC) </= 105 latidos por minuto (lpm) en las 2 primeras horas después de tomar la dois de sildenafilo (medidas a Visitas 0 y 1).
    ?Pueden ser incluidas en el estudio mujeres no fértiles, definidas como mujeres postmenopaúsicas (es decir con ausencia de periodos mensuales durante más de 2 años), mujeres con ligadura bilateral de trompas, mujeres con ovariectomía bilateral y mujeres con histerectomía. Las mujeres en edad fértil solo pueden incluirse en el estudio si la prueba de embarazo serológica ha sido negativa y si se utiliza una combinación segura de 2 métodos anticonceptivos durante todo el estudio (p.ej. prescripción de anticonceptivos orales, anticonceptivos injectables, parches anticonceptivos, dispositivos intrauterinos, doble barrera anticonceptiva, esterilización de la pareja varón).
    ?Pacientes con capacidad para entender y seguir las instrucciones y que sean capaces de participar en el estudio durante el periodo completo de duración del mismo.
    ?Los pacientes deben haber otorgado el consentimiento informado por escrito para participar en el estudio después de haber recibido la información previa pertinente y antes de someterse a cualquier procedimiento específico del estudio.
    E.4Principal exclusion criteria
    ?Subject´s participating in another clinical trial or who have done so within 30 days before Visit 1.
    ?Previous assignment to treatment during this study.
    ?Pregnant women (ie positive serum beta-human-chorionic-gonadotropin test or other signs of pregnancy), or breast feeding women, or women with childbearing potential not using a combination of 2 effective methods of birth control (eg prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method, male partner sterilization) throughout the study.
    ?Subjects with a medical disorder, condition, or history of such that would impair the subject´s ability to participate or complete this study in the opinion of the investigator.
    ?Subjects with substance abuse (eg alcohol or drug abuse) within the previous 180 days before Visit 1.
    ?Subjects with underlying medical disorders with an anticipated life expectancy below 2 years (eg active cancer disease with localized and/or metastasized tumor mass).
    ?Subjects with a history of severe allergies or multiple drug allergies.
    ?Subjects with hypersensitivity to the investigational drug or any of the excipients.
    ?Subjects unable to perform a valid 6MWD test, eg subjects with a severe peripheral artery occlusive disease.
    (Note: Subjects, who require walking aids, may be included if in the opinion of the investigator the walking distance is not impaired.)
    ?Subjects with a relative difference (ie absolute difference/mean) of more than 15% between the eligibility- and the baseline 6MWD test
    ?All types of pulmonary hypertension except subtypes of Updated Clinical Classification of PH (Dana Point 2008) Group I specified in the inclusion criteria.
    ?Moderate to severe obstructive lung disease (forced expiratory volume <60% predicted). The predicted forced expiratory volume in 1 second (FEV1) is a calculated value.
    ?Severe restrictive lung disease (total lung capacity <70% predicted). The predicted total lung capacity (TLC) is a calculated value.
    ?Severe congenital abnormalities of the lungs, thorax, and diaphragm.
    ?Oxygen saturation (SaO2) <88% despite supplemental oxygen therapy.
    ?Arterial partial oxygen pressure (PaO2) <55 mmHg despite supplemental oxygen therapy.
    ?Arterial partial pressure of carbon dioxide (PaCO2) >45 mmHg.
    ?Uncontrolled arterial hypertension (SBP >180 mmHg and /or diastolic blood pressure >110 mmHg).
    ?Atrial fibrillation within the last 90 days before Visit 1.
    ?Pulmonary venous hypertension with pulmonary capillary wedge pressure >15 mmHg.
    ?Hypertrophic obstructive cardiomyopathy.
    ?Severe proven or suspected coronary artery disease (subjects with Canadian Cardiovascular Society Angina Classification class 2 to 4, and/or requiring nitrates, and/or myocardial infarction within the last 90 days before Visit 1).
    ?Clinical evidence of symptomatic atherosclerotic disease (eg peripheral artery disease with reduced walking distance, history of stroke with persistent neurological deficit etc).
    ?Congenital or acquired valvular or myocardial disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension.
    ?Clinical relevant hepatic dysfunction indicated by:
    - Bilirubin >2 times upper limit normal (ULN)
    - and/or ALT (alanine aminotransferase) or AST (aspartate aminotransferase) >3 times ULN
    - and/or signs of severe hepatic insufficiency (eg impaired albumin synthesis with an albumin <32 g/L, hepatic encephalopathy > grade 1.
    ?Renal insufficiency (glomerular filtration rate <30 mL/min, eg calculated based on the Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formulas
    ?Pacientes que estén participando en otro estudio clínico o que lo haya hecho en los 30 días previos a la Visita .
    ?Pacientes que previamente hayan sido asignados a tratamiento durante el estudio.
    ?Mujeres embarazadas, (es decir el test de embarazo positivo para gonadotropina coriónoca humana ? sérica u otros signos de embarazo),o en periodo de lactancia, o mujeres en edad fértil que no usen una combinación segura de 2 métodos anticonceptivos durante el estudio (p.ej. prescripción de anticonceptivos orales, anticonceptivos injectables, parches anticonceptivos, dispositivos intrauterinos, doble barrera anticonceptiva, esterilización de la pareja varón).
    ?Pacientes que, a juicio del investigador, experimentan un trastorno clínico, enfermedad o antecedentes que puedan deteriorar su capacidad para participar o completar este estudio.
    ?Pacientes con abuso de substancias (ej, alcohol o abuso de drogas) en los 180 días previos a la Visita 1.
    ?Pacientes con trastornos clínicos subyacentes con una esperanza de vida prevista inferior a 2 años (p.ej. enfermedad cancerígena activa con masas tumorales localizadas y/o metastásicas).
    ?Pacientes con historia de alergia severa o alergias a varios fármacos.
    ?Pacientes con hipersensibilidad al medicamento en investigación o a cualquiera de los excipientes.
    ?Pacientes incapaces de efectuar la prueba de 6MWD, p.ej. pacientes con enfermedad oclusiva arterial periférica severa.
    (Nota: Los pacientes que requieran ayuda para caminar pueden incluirse siempre que, en la opinión del investigador la distancia recorrida no se vea afectada.)
    ?Pacientes con una diferencia relativa (es decir diferencia absoluta / media) de más del 15% entre la prueba de elegibilidad y la prueba basal 6MWD.
    ?Todos los tipos de hipertensión pulmonar salvo los subtipos del Grupo I de la Clasificación Clínica de Hipertensión Pulmonar (Dana Point 2008) especificados en los criterios de inclusión.
    ?Enfermedad pulmonar obstructiva entre moderada y severa (Volumen de espiración forzado en un segundo < 60% del previsto). El Volumen de Espiración Forzado Previsto en un segundo (FEV1) es un valor calculado.
    ?Enfermedad pulmonar restrictiva severa (Capacidad pulmonar total < 70% del previsto). La capacidad pulmonar total (TLC) es un valor calculado.
    ?Anomalías congénitas severas en pulmón, tórax y diafragma.
    ?Saturación de Oxigeno (SaO2) < 88% a pesar de terapia con suplemento de oxígeno.
    ?Presión parcial arterial de oxígeno(PaO2)< 55 mmHg a pesar de terapia con suplemento de oxígeno.
    ?Presión parcial arterial de dióxido de carbono (PaCO2) > 45 mmHg.
    ?Hipertensión arterial no controlada (PAS >180 mmHg y/o Presión arterial diastólica >110mmHg).
    ?Fibrilación auricular ó aleteo auricular en los últimos 90 días previos a la Visita 1.
    ?Hipertensión venosa pulmonar indicada por una presión de enclavamiento capilar pulmonar basal >15 mmHg.
    ?Cardiomiopatía obstructiva hipertrófica.
    ?Arteriopatía coronaria severa demostrada o sospechada (pacientes con clasificación de angina por la sociedad cardiovascular canadiense de tipo 2-4, y/o que requieran nitratos y/o infarto de miocardio en los 90 días previos a la Visita 1).
    ?Evidencia clínica de enfermedad aterosclerótica sintomática (p.ej. arteriopatía periférica con reducción de la distancia caminando, historia de accidente cerebrovascular con déficit neurológico persistente, etc).
    ?Enfermedad valvular o miocárdica, congénita o adquirida, si es clínicamente significativa, salvo insuficiencia de la válvula tricúspide debida a hipertensión pulmonar.
    ?Insuficiencia hepática clínica relevante indicada por:
    - bilirrubina >2 veces el límite máximo de los valores normales
    - y / o ALT (Alanina aminotransferasa) ó AST (Aspartato aminotransferasa ) >3 veces el límite máximo de los valores normales.
    - y / o signos de insuficiencia hepática severa (por ejemplo alteración en la síntesis de albúmina, con albúmina < 32g/l, encefalopatía hepática > grado 1.)
    ?Insuficiencia renal grave (tasa de filtración glomerular <30 mL/min, p.ej. calculado basándose en las fórmulas de Cockcroft o de Modification of Diet in Renal Disease (MRDS)
    E.5 End points
    E.5.1Primary end point(s)
    Maximum change in supine SBP from baseline within 4 h of dosing with riociguat for the individual dose steps or placebo.
    Máximo cambio respecto al valor basal de la presión arterial sistémica en las 4 horas de la titulación de dosis con riociguat o placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every two weeks over 8 weeks
    Cada dos semanas durante 8 semanas.
    E.5.2Secondary end point(s)
    Secondary pharmacodynamic endpoints:
    - Maximum change in standing diastolic blood pressure (DBP) from baseline within 4 h of dosing with study medication.
    - Maximum change in supine DBP from baseline within 4 h of dosing with study medication.
    - Maximum change in supine and standing HR from baseline within 4 h of dosing with study medication.
    - Area under effect curve (AUEC) for change from baseline in standing and supine systolic and diastolic BP, and HR within 6 h of dosing with riociguat or placebo.
    Exploratory efficacy endpoints:
    - Change from baseline in 6MWD after 12 weeks.
    - Change from baseline in NT-proBNP after 12 weeks.
    - Change from baseline in WHO functional class after 12 weeks.
    - Time to clinical worsening.
    - Change from baseline in Borg CR 10 scale (measured at the end of the 6MWD test) after 12 weeks.
    Safety endpoints:
    Safety of riociguat/sildenafil combination.
    Criterios secundarios de farmacodinámica:
    -Cambio máximo respecto a la basal de la presión arterial sistólica (PAS) en posición de pie dentro de las 4 horas de la dosis con la medicación del estudio.
    -Cambio máximo respecto a la basal de la presión arterial diastólica (PAD) en posición de pie dentro de las 4 horas de la dosis con la medicación del estudio.
    -Cambio máximo respecto a la basal de la FC en posición supina y de pie dentro de las 4 horas de la dosis con la medicación del estudio.
    -Area debajo de la curva de efecto (AUEC) para el cambio respecto a la basal en posción supina y de pied de la PA sistólica y diastólica, y FC dentro de las 6 horas de la dosis de riociguat o placebo.
    Criterios exploratorios de eficacia:
    -Cambios respecto a la basal en el 6MWD después de 12 semanas.
    -Cambios respecto a la basal en el NT-proBNP después de 12 semanas.
    -Cambios respecto a la basal en al Clase funcional de la OMS después de 12 semanas.
    -Tiempo hasta el empeoramiento clínico
    -Cambios respecto a la basal en la escala Borg CR10 (determinada al finalizar la prueba de 6MWD) después de 12 semanas:
    Criterios de seguridad:
    -Seguridad de la combinación riociguat/sildenafilo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary pharmacodynamic endpoints
    Every 2 weeks over 8 weeks:
    -Maximum change in standing SBP...
    -Maximum change in standing diastolic blood pressure...
    -Maximum change in supine DBP...
    -Maximum change in supine and standing HR...
    Within 6 h of dosing with riociguat or placebo:
    -AUEC for change from baseline in standing and supine systolic and diastolic BP, and HR
    Exploratory efficacy endpoints:
    After 12 weeks:
    -Change from baseline in 6MWD
    -Change from baseline in NT-proBNP
    -Change from baseline in WHO functional class
    -Time to clinical worsening.
    -Change from baseline in Borg CR 10 scale
    Safety endpoints:
    At every visit
    Criterios secundarios de farmacodinámica
    Cada dos semanas durante 8 semanas:
    -Cambio máximo en la PAS en posición de pie...
    -Cambio máximo en la presión arterial diastólica de pie...
    -Cambio máximo en la PAD en posición supina...
    -Cambio máximo en la FC en posción supina y de pie...
    Dentro de las 6 h de la dosis de riociguat o placebo:
    -Cambio de la AUEC respecto a la basal en posición supina y de pie de la PA sistólica y diastólica, y de la FC.
    Criterios exploratorios de eficacia:
    Desoués de 13 semanas:
    -Cambio respecto a la basal del 6MWD
    -Cambio respecto a la basal en NT-proBNP
    -Cambio respecto a la basal en la clase funcional de la OMS
    -Tiempo hasta el empeoramiento clínico
    -Cambio respecto a la basal de la escla Borg CR10
    Criterios de seguridad:
    En cada visita
    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 Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    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 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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    Last visit of the last patient undergoing the trial.
    Ultima visita del ultimo paciente en el estudio
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months11
    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 months9
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 36
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 36
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2011-06-20. Yes
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 36
    F.4.2.2In the whole clinical trial 36
    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)
    After the 12 weeks treatment, patients may enter long-term extension study and be treated until riociugat is approved and reimbursed.
    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 Decision2011-07-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-07-22
    P. End of Trial
    P.End of Trial StatusCompleted
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA