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    Summary
    EudraCT Number:2012-002104-40
    Sponsor's Protocol Code Number:BAY63-2521/16097
    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:2013-02-04
    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 number2012-002104-40
    A.3Full title of the trial
    An open-label phase IIIb study of riociguat in patients with in-operable CTEPH, or recurrent or persisting PH after surgical treatment who are not satisfactorily treated and cannot participate in any other CTEPH trial
    Estudio abierto de fase IIIb con Riociguat en pacientes con Hipertensión Pulmonar Tromboembólica Crónica (HPTEC), o con Hipertensión Pulmonar (HP) recurrente o persistente, después del tratamiento quirúrgico que no están tratados satisfactoriamente y no pueden participar en otro estudio en HPTEC
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    To assess safety and tolerability, clinical effects of riociguat.
    To provide access to riociguat for patients with in-operable chronic thromboembolic pulmonary hypertension (CTEPH), or recurrent or persisting pulmonary hypertension (PH) after surgical treatment who are not satisfactorily treated and cannot participate in any other CTEPH trial.
    Evaluar la seguridad, tolerabilidad y los efectos clínicos de riociguat.
    Proporcionar acceso a riociguat a los pacientes con hipertensión pulmonar tromboembólica crónica (HPTEC) inoperable o con hipertensión pulmonar (HP) persistente o recurrente después de la cirugía que no están tratados satisfactoriamente y no pueden participar en otro estudio sobre la HPTEC
    A.3.2Name or abbreviated title of the trial where available
    Phase IIIb study of riociguat in patients with chronic thromboembolic pulmonary hypertension
    Estudio de fase IIIb sobre riociguat en pacientes con hipertensión pulmonar tromboembólica crónica.
    A.4.1Sponsor's protocol code numberBAY63-2521/16097
    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 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 pointBayer Clincal Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressCTP Team/Ref:"EUCTR"/Bayer Pharma AG
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.4Telephone number+4930300139003
    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 tablet 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 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: 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 tablet 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 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: 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 tablet 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 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: 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 tablet 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 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: 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 tablet 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 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.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
    Chronic Trombo Embolic Pulmonary Hypertention
    Hipertensión Pulmonar Tromboembólica Crónica (HPTEC)
    E.1.1.1Medical condition in easily understood language
    Persistent pulmonary hypertension caused by obstruction of a major pulmonary artery by an unresolved embolus or multiple small pulmonary emboli.
    Hipertensión pulmonar persistente causada por una obstrucción de la arteria pulmonar mayor debid a un trombo no resuelto o a múltimples embolos pulmonares pequeños.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10068740
    E.1.2Term CTEPH
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To assess safety and tolerability, clinical effects of riociguat
    - To provide access to riociguat for patients with in-operable chronic thromboembolic pulmonary hypertension (CTEPH), or recurrent or persisting pulmonary hypertension (PH) after surgical treatment who are not satisfactorily treated and cannot participate in any other CTEPH trial.
    - Evaluar la seguridad, tolerabilidad y los efectos clínicos de riociguat.
    - Proporcionar acceso a riociguat a los pacientes con hipertensión pulmonar tromboembólica crónica (HPTEC) inoperable o con hipertensión pulmonar (HP) persistente o recurrente después de la cirugía que no están tratados satisfactoriamente y no pueden participar en otro estudio sobre la HPTEC.
    E.2.2Secondary objectives of the trial
    "Not Applicable"
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - 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.
    - 18 to 80 years of age at screening
    - Patients with inoperable CTEPH
    - The diagnosis is based on (performed max. 1 year prior to screening)
    o Historical pulmonary angiogram , and/or
    o CT or MR pulmonary angiogram , and/or
    o Ventilation /Perfusion (V/Q) Scan AND
    o Historical right heart catheter test (performed max. 1 year prior to screening) confirming mean pulmonary arterial pressure (mPAP) > 25 mmHg
    o Patients on full anti-coagulation therapy for at least 3 months prior to entry into study
    o Diagnosis has to be confirmed by a surgeon/physician experienced in diagnosing and treating CTEPH (see Declaration of Experienced Investigator or Surgeon/Physician in Appendix 14.5.2)
    - Post-PEA patients with recurrent or residual PH having at least 90 days of full anti-coagulation after surgery
    o Right heart catheter (RHC) test measured 180 days after surgery confirming:
    o mPAP > 25 mmHg and pulmonary capillary wedge pressure (PCWP) <= 15 mmHg
    o Pulmonary vascular resistance (PVR)>300 dyn*sec*cm-5
    - No treatment with riociguat or PDE5-inhibitor, endothelin receptor antagonist (ERA) or prostanoid with a minimum time frame of at least 3 days, or more at the discretion of the investigator prior to start of riociguat treatment.
    - Patients who are able to understand and follow instructions and who should be able to participate in the study for the entire period.
    - Unspecific treatments which may also be used for the treatment of pulmonary hypertension such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation are permitted. However, treatment with anticoagulants must have been started at least 90 days before Week 0 (Visit 1)
    - Women without childbearing potential defined as postmenopausal women (= 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 can only be included in the study if a serological pregnancy test is negative and a combination of safe contraception methods is used throughout the study.
    - Women of childbearing potential and men must agree to use adequate contraception when sexually active. This applies since signing of the informed consent form until the time point of safety follow-up of 30 days after the last study drug administration. Acceptable methods of contraception include (i) condoms (male or female) with or without a spermicidal agent; (ii) diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv) hormone-based contraception
    - Los pacientes deben haber firmado el consentimiento informado por escrito para participar en el estudio tras haber recibido la información adecuada y antes de realizar cualquier procedimiento específico del estudio.
    - Pacientes de 18 a 80 años en el momento de la selección
    - Pacientes con HPTEC inoperable
    - El diagnóstico se basa en (realizado como máximo 1 año antes de la selección)
    o Angiografía pulmonar realizada con anterioridad, y/o
    o Angiografía pulmonar por TC o RM, y/o
    o Gammagrafía de ventilación y perfusión (V/P) Y
    o Cateterismo cardíaco derecho realizado con anterioridad (realizado como máximo 1 año antes de la selección) en el que se confirme una presión arterial pulmonar media (PAPm) > 25 mm Hg
    o Pacientes con tratamiento anticoagulante completo durante al menos los 3 meses previos a la inclusión en el estudio
    o El diagnóstico lo debe confirmar un cirujano/médico con experiencia en el diagnóstico y el tratamiento de la HPTEC (véase la Declaración sobre la experiencia del investigador o cirujano/médico en el Anexo 14.5.2)
    - Pacientes con HP recurrente o residual tras una EP que hayan recibido al menos 90 días de anticoagulación completa tras la cirugía
    o Cateterismo cardíaco derecho (CCD) a los 180 días de la cirugía en el que se confirme:
    o PAPm > 25 mm Hg y presión de enclavamiento capilar pulmonar (PECP) menor o igual a 15 mm Hg
    o Resistencia vascular pulmonar (RVP) > 300 dina*s*cm-5
    - Ningún tratamiento con riociguat o con inhibidores de PDE5, antagonistas del receptor de endotelina (ARE) o prostanoides en un intervalo mínimo de tiempo de al menos 3 días, o más según el criterio del investigador, antes del inicio del tratamiento con riociguat.
    - Pacientes que sean capaces de entender y seguir las instrucciones y que puedan participar en el estudio durante todo el periodo.
    - Están permitidos los tratamientos inespecíficos que también se puedan utilizar para el tratamiento de la hipertensión pulmonar, como anticoagulantes orales, diuréticos, digitálicos, antagonistas del calcio o suplementos de oxígeno. Sin embargo, el tratamiento con anticoagulantes se debe haber iniciado al menos 90 días antes de la semana 0 (visita 1)
    - Se pueden incluir en este estudio a mujeres sin capacidad reproductora, definidas como mujeres posmenopáusicas (= ausencia permanente de periodos mensuales durante más de 2 años), mujeres con ligadura de trompas bilateral, mujeres con ovariectomía bilateral y mujeres con histerectomía. Las mujeres con capacidad reproductora solo podrán ser incluidas en el estudio si se obtiene un resultado negativo en una prueba de embarazo en suero y se utiliza una combinación de métodos anticonceptivos seguros durante el estudio.
    - Las mujeres con capacidad reproductora y los hombres deberán aceptar el uso de métodos anticonceptivos adecuados cuando sean sexualmente activos. Esto será de aplicación desde la firma del documento de consentimiento informado hasta el momento del seguimiento de seguridad a los 30 días de la última administración del fármaco del estudio. Los métodos anticonceptivos aceptables incluyen (i) preservativos (masculino o femenino) con o sin espermicida; (ii) diafragma o capuchón cervical con espermicida; (iii) dispositivo intrauterino; (iv) métodos anticonceptivos hormonales.
    E.4Principal exclusion criteria
    General exclusions
    - All types of pulmonary hypertension except the one according to the Dana Point Classification Group 4 (1)
    - Pregnant women, or breast feeding women, or women with childbearing potential not using a combination of condoms and a safe and highly effective contraception method (hormonal contraception with implants or combined oral contraceptives, certain IUDs).
    - Patients participating in another clinical trial or who have done so within 4 weeks before screening.
    - Patients with hypersensitivity to the investigational drug or any of the excipients.
    Pulmonary diseases exclusions
    - Operable patients listed for PEA
    - Patients listed for urgent lung transplantation.
    Medication/treatment exclusions
    - Chronic treatment with NO-donors (e.g., nitrates at any time) less or equal to 3 days prior to prior to start of riociguat treatment .
    - Phosphodiesterase type 5 (PDE-5) inhibitors, ERAs and prostanoids* less or equal to 3 days days prior to prior to start of riociguat treatment .

    *Single applications of vasoactive drugs in connection with diagnostic vasoreactive testing (e.g. prostacyclines) need not to be considered
    - If the above medication/treatment exclusions are deemed to be medically required in the opinion of the investigator, the patient cannot be enrolled in the study.
    Cardiovascular and pulmonary exclusions
    - Uncontrolled arterial hypertension (Systolic blood pressure -180 mmHg and /or diastolic blood pressure >110 mmHg).
    - Systolic blood pressure <95 mmHg.
    - Resting heart rate in the awake patient <50 beats per minute (BPM) or >105 BPM.
    - History of uncontrolled atrial fibrillation within the last 3 months before screening.
    - Left heart failure with an ejection fraction less than 40%.
    - Pulmonary venous hypertension with pulmonary capillary wedge pressure >15 mmHg.
    - Hypertrophic obstructive cardiomyopathy.
    - Severe proven or suspected coronary artery disease (patients with Canadian Cardiovascular Society Angina Classification class 2-4, and/or requiring nitrates, and/or myocardial infarction within the last 3 months before screening).
    - Clinical evidence of symptomatic atherosclerotic disease (e.g. peripheral artery disease).
    - History of stroke within last 3 months prior to screening.
    - Congenital or acquired valvular or myocardial disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension. Evidence for recurrent thromboembolism despite sufficient (documented) oral anticoagulation - also when pulmonary arteries are not affected.

    - History or active state of serious hemoptysis / pulmonary hemorrhage including those managed by bronchial artery embolization.

    Exclusion criteria related to disorders in organ function
    - clinical relevant hepatic dysfunction indicated by:
    o Bilirubin >2 times upper limit normal (ULN) at screening and/or
    o ALT (alanine aminotransferase) or AST (aspartate aminotransferase) >3 times ULN at screening and/or
    o Signs of severe hepatic insufficiency (e.g. impaired albumin synthesis with an albumin <2 g/L, hepatic encephalopathy > grade 1 according to West Haven Criteria of Altered Mental Status in Hepatic Encephalopathy [7]) at screening.
    - Renal insufficiency (glomerular filtration rate <30 mL/min, e.g. calculated based on the Cockcroft-Gault formulas at screening.
    Exclusiones generales
    - Todos los tipos de hipertensión pulmonar excepto la que corresponda al grupo 4 de clasificación de Dana Point (1)
    - Mujeres embarazadas o en periodo de lactancia, o mujeres con capacidad reproductora que no utilicen una combinación de preservativos y un método anticonceptivo seguro y altamente eficaz (anticoncepción hormonal con implantes o anticonceptivos orales combinados, determinados
    DIU).
    - Pacientes que participen en otro estudio clínico o que hayan participado en las 4 semanas previas a la selección.
    - Pacientes con hipersensibilidad al fármaco en investigación o a alguno de los excipientes.
    Exclusiones por enfermedades pulmonares
    - Pacientes operables en lista de espera para EP
    - Pacientes en lista de espera para trasplante pulmonar urgente.
    Exclusiones por medicación/tratamiento
    - Tratamiento crónico con donantes de NO (p. ej., nitratos en cualquier momento) menos o igual a 3 días antes del inicio del tratamiento con riociguat.
    - Inhibidores de la fosfodiesterasa de tipo 5 (PDE5), ARE y prostanoides* menos o igual a 3 días antes del inicio del tratamiento con riociguat.
    *No se tendrán en cuenta aplicaciones únicas de fármacos vasoactivos en relación con una prueba de vasorreactividad (p. ej., prostaciclinas).
    - Si las exclusiones por medicación/tratamiento anterior se consideran necesarias desde el punto de vista médico, según el criterio del investigador, no se podrá incluir al paciente en el estudio.
    Exclusiones cardiovasculares y pulmonares
    - Hipertensión arterial no controlada (presión arterial sistólica > 180 mm Hg y/o presión arterial diastólica > 110 mm Hg).
    - Presión arterial sistólica < 95 mm Hg.
    - Frecuencia cardíaca en reposo con el paciente despierto < 50 latidos por minuto (lpm) o > 105 lpm.
    - Antecedentes de fibrilación auricular no controlada en los últimos 3 meses previos a la selección.
    - Insuficiencia ventricular izquierda con una fracción de eyección menor del 40 %.
    - Hipertensión venosa pulmonar con una presión de enclavamiento capilar pulmonar > 15 mm Hg.
    - Miocardiopatía hipertrófica obstructiva.
    - Arteriopatía coronaria grave diagnosticada o sospechada (pacientes con clase 2 - 4 en la clasificación de la de la angina de la Canadian Cardiovascular Society, y/o que necesitan nitratos, y/o infarto de miocardio en los últimos 3 meses previos a la selección).
    - Signos clínicos de enfermedad aterosclerótica sintomática (p. ej., arteriopatía periférica).
    - Antecedentes de ictus en los 3 meses previos a la selección.
    - Enfermedad miocárdica o valvular congénita o adquirida si es clínicamente significativa, excepto insuficiencia de la válvula tricúspide debida a hipertensión pulmonar. Signos de tromboembolia recurrente a pesar de anticoagulación oral suficiente (documentada), aun cuando no estén afectadas las arterias pulmonares.
    - Antecedentes o estado activo de hemoptisis/hemorragia pulmonar grave, incluidas las provocadas por embolización arterial bronquial.
    Criterios de exclusión relacionados con alteraciones en la función orgánica
    - Disfunción hepática clínicamente relevante indicada por:
    o Bilirrubina > 2 veces el límite superior de la normalidad (LSN) en la selección y/o
    o ALT (alanina-aminotransferasa) o AST (aspartato-aminotransferasa) > 3 veces el LSN en la selección y/o
    o Signos de insuficiencia hepática grave (p. ej., alteración de la síntesis de albúmina con un nivel de albúmina < 32 g/l, encefalopatía hepática > grado 1 según los Criterios de West Haven para la valoración del estado mental en la encefalopatía hepática [7]) en la selección.
    - Insuficiencia renal (filtración glomerular < 30 ml/min), p. ej., calculada a partir de las fórmulas de Cockcroft-Gault en la selección.
    E.5 End points
    E.5.1Primary end point(s)
    This is open-label long- term surveillance study safety and tolerability as well as clinical effects will be measured.
    En este estudio abierto de vigilancia se medirán la seguridad, tolerabilidad y efectos clínicos.
    E.5.1.1Timepoint(s) of evaluation of this end point
    In general, data will be displayed as measured at each scheduled time point and individual values will be presented as well as the corresponding changes from baseline (change value = post-baseline value ? baseline value).
    En general, los datos se monitorizarán en cada visita programada, se presentarán los valores individuales así como los cambios respecto a los valores basales (cambio valor= post- valor basal vs valor basal)
    E.5.2Secondary end point(s)
    Not Applicable
    E.5.2.1Timepoint(s) of evaluation of this end point
    Not Applicable
    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) 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 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) 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 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 EEA50
    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
    Austria
    Belgium
    Brazil
    Canada
    Czech Republic
    Denmark
    France
    Germany
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    Portugal
    Russian Federation
    Spain
    Sweden
    Switzerland
    Turkey
    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
    As for the study, the primary outcome will be analyzed after last patient last visit, the end of the study as a whole will be the date when the clean data base is available.
    Por protocolo, el resultado final se analizará después del último paciente última visita, el estudio se considerará como completo en la fecha en la que la base de datos limpia esté disponible.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 300
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 500
    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)
    If the investigator deems appropriate treatement for the patient, treatment will be continued until Riociguat is approved and commercially available.
    Si el Investigador considera el tratamiento apropiado para el paciente, el tratamiento se continuará hasta que Riociguat sea aprobado y esté comercialmente disponible.
    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 Decision2013-04-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-03-15
    P. End of Trial
    P.End of Trial StatusCompleted
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