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    Summary
    EudraCT Number:2013-004362-34
    Sponsor's Protocol Code Number:A1481324
    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:2014-05-08
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2013-004362-34
    A.3Full title of the trial
    A MULTINATIONAL, MULTICENTER STUDY TO ASSESS THE EFFECTS OF ORAL SILDENAFIL ON MORTALITY IN ADULTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH)
    ESTUDIO MULTICÉNTRICO MULTINACIONAL PARA EVALUAR LOS EFECTOS DE SILDENAFILO ORAL SOBRE LA MORTALIDAD DE ADULTOS CON HIPERTENSIÓN ARTERIAL PULMONAR (HAP)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A MULTINATIONAL, MULTICENTER STUDY TO ASSESS THE EFFECTS OF ORAL SILDENAFIL ON MORTALITY IN ADULTS WITH PULMONARY ARTERIAL HYPERTENSION
    ESTUDIO MULTICÉNTRICO MULTINACIONAL PARA EVALUAR LOS EFECTOS DE SILDENAFILO ORAL SOBRE LA MORTALIDAD DE ADULTOS CON HIPERTENSIÓN ARTERIAL PULMONAR
    A.4.1Sponsor's protocol code numberA1481324
    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 SponsorPfizer Inc., 235 East 42nd Street, New York, NY 10017
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPfizer Inc., 235 East 42nd Street, New York, NY 10017
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinicalTrials.gov Call Centre
    B.5.3 Address:
    B.5.3.1Street Address235 E 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1800 7181021
    B.5.5Fax number+1303 7391119
    B.5.6E-mailClinicalTrials.gov.CallCenter@pfizer.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 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/03/178
    D.3 Description of the IMP
    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
    D.3.9.3Other descriptive nameSILDENAFIL CITRATE
    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.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/3/03/178
    D.3 Description of the IMP
    D.3.1Product nameSildenafil
    D.3.2Product code UK 092480
    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
    D.3.9.3Other descriptive nameSILDENAFIL CITRATE
    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 number5
    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/3/03/178
    D.3 Description of the IMP
    D.3.1Product nameSildenafil
    D.3.2Product code UK 092480
    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
    D.3.9.3Other descriptive nameSILDENAFIL CITRATE
    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 number80
    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
    D.8 Placebo: 2
    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
    D.8 Placebo: 3
    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 Arterial Pulmonar
    E.1.1.1Medical condition in easily understood language
    Pulmonary Arterial Hypertension
    Hipertensión Arterial Pulmonar
    E.1.1.2Therapeutic area Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective: Test for the non-inferiority of sildenafil 80 mg vs. 5 mg for mortality; mortality rate with the 80 mg dose is no worse than double the mortality rate for the 5 mg dose.
    Objetivo principal: Evaluar la no inferioridad de sildenafilo 80 mg en comparación con 5 mg respecto a la mortalidad; la tasa de mortalidad con la dosis de 80 mg no es peor que el doble de la tasa de mortalidad con la dosis de 5 mg
    E.2.2Secondary objectives of the trial
    Not applicable
    No aplicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
    1. Subjects ? 18 and <75 years of age with any of the following conditions:
    a. Idiopathic Pulmonary Arterial Hypertension (IPAH); or
    b. PAH secondary to connective tissue disease (CTD); or
    c. PAH with surgical repair (at least 5 years previously) of atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA) and aorto-pulmonary window.
    2. PAH must have been newly diagnosed by right heart catheterization within 12 months prior to randomization (mean pulmonary artery pressure (mPAP) ?25 mmHg at rest, pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ?15 mmHg, and pulmonary vascular resistance (PVR) >4 mmHg/L/min or 320 dynes*sec/cm5);
    3. No prior PDE-5 inhibitor treatment for PAH (Prior episodic use of PDE-5 inhibitors for erectile dysfunction does not disqualify a subject from the study);
    4. PAH WHO Functional Class II-IV;
    5. Baseline 6MWD ?50 m.
    6. Male or female subjects not of childbearing potential or female subjects of childbearing potential who agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of assigned treatment. Female subjects who are not of childbearing potential include those who meet at least one of the following criteria:
    a. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
    b. Have medically confirmed ovarian failure or;
    c. Achieved post-menopausal status, defined as the cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause and a serum FSH level within the laboratory's reference range for postmenopausal females.
    7. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures; and
    8. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
    Para ser aptos para inscribirse en el estudio, los sujetos deben cumplir todos los criterios de inclusión siguientes:
    1. Sujetos ? 18 y < 75 años de edad que presenten cualquiera de las afecciones siguientes:
    a. Hipertensión arterial pulmonar idiopática (HAPI); o
    b. HAP como consecuencia de enfermedad del tejido conjuntivo (ETC); o
    c. HAP con reparación quirúrgica (por lo menos 5 años antes) de comunicación interauricular (CIA), comunicación interventricular (CIV), conducto arterioso persistente (CAP) y ventana aortopulmonar.
    2. La HAP debe haber sido diagnosticada recientemente por medio de cateterismo de cavidades derechas en los 12 meses anteriores a la aleatorización (presión arterial pulmonar media (PAPm) ?25 mmHg en reposo, presión capilar pulmonar (PCP) o presión de fin de diástole ventricular izquierda (PFDVI) ?15 mmHg, y resistencia vascular pulmonar (RVP) >4 mmHg/l/min o 320 dinas*seg/cm5);
    3. Ningún tratamiento anterior con inhibidores de la PDE-5 para la HAP (el uso ocasional anterior de inhibidores de la PDE-5 para la disfunción eréctil no inhabilita a un sujeto para participar en el estudio);
    4. Clase funcional II-IV de la OMS de la HAP;
    5. PC6M inicial ?50 m.
    6. Sujetos mujeres o varones que no puedan procrear o sujetos mujeres con capacidad para procrear que acepten usar un método anticonceptivo de alta eficacia durante todo el estudio y durante por lo menos 28 días después de la última dosis del tratamiento asignado. Las participantes mujeres que no puedan procrear incluyen a quienes cumplan por lo menos uno de los siguientes criterios:
    a. Se hayan sometido a histerectomía y/u ovariectomía documentada;
    b. Tengan insuficiencia ovárica médicamente confirmada o;
    c. Hayan llegado a la etapa posmenopáusica, definida como el cese de períodos menstruales normales durante al menos 12 meses consecutivos sin ninguna causa alternativa patológica ni fisiológica y una concentración sérica de FSH dentro del intervalo de referencia de los valores de laboratorio para mujeres posmenopáusicas.
    7. Estén dispuestas y en condiciones de cumplir con las visitas programadas, el plan de tratamiento, los análisis clínicos y los procedimientos el ensayo; y
    8. Muestren un documento de consentimiento informado fechado y firmado personalmente que indique que el sujeto (o un representante legal) ha recibido información sobre todos los aspectos relacionados con el estudio.
    E.4Principal exclusion criteria
    Subjects presenting with any of the following will not be included in the study:
    1. PAH secondary to any etiology other than those specified in the inclusion criteria;
    2. Significant (ie, >2+) valvular disease other than tricuspid regurgitation or pulmonary regurgitation;
    3. Congenital heart disease (unless they meet inclusion criteria in Section 4.1 or pulmonary hypertension due to thromboembolism;
    4. Atrial septostomy within 6 months prior to randomization (subjects who are required to undergo this procedure during the study should be withdrawn);
    5. Myocardial infarction, unstable angina, cerebrovascular accident (CVA), or transient ischemic attack (TIA) within 6 months prior to randomization;
    6. Acutely decompensated heart failure within 3 months prior to randomization;
    7. History of cardiac arrest, respiratory arrest, hemodynamic collapse, CPR, ventricular tachycardia, ventricular fibrillation, or permanent atrial fibrillation;
    8. History of pulmonary embolism verified by ventilation/perfusion scan, angiogram or spiral chest computerized tomography scan;
    9. Hypotension defined as systolic arterial pressure <90 mmHg or diastolic arterial pressure <50 mmHg after sitting for 5 minutes at either Screening or Day 1;
    10. Treatment with PDE-5 inhibitors for PAH (Prior episodic use of PDE-5 for erectile dysfunction does not disqualify a subject.);
    11. Treatment with bosentan within 3 months of randomization;
    12. Current treatment with nitrates or nitric oxide;
    13. Initiation of new therapy for PAH <3 months prior to randomization or change in background treatment specific for PAH within 30 days prior to randomization (ie, ambrisentan and any other ETRA that becomes available during the conduct of the study provided that the new agent is not a potent CYP3A inducer or inhibitor (Appendix 1) that has a clinically evident drug-drug interaction with sildenafil and/or prostanoids);
    14. Change in class of supportive therapy used for adjunctive treatment of PAH within 30 days prior to randomization (eg, oxygen, calcium channel blockers, digoxin, diuretics);
    15. Current treatment with potent CYP3A4 inhibitors or inducers (Appendix 1);
    16. History of chronic lung disease / restrictive lung disease (eg, chronic obstructive pulmonary disease (COPD) or scleroderma) with impairment of lung function demonstrated by total lung capacity (TLC) <70% predicted, or forced expiratory volume (FEV1) <60% predicted. (Subjects with these pulmonary disorders must have Pulmonary Function Tests performed prior to study entry if they have not been performed in the previous 12 months);
    17. Within 5 years of Screening, history of malignancy (except for adequately treated basal cell or squamous cell carcinoma of the skin), human immunodeficiency virus (HIV) or any other disease likely to limit life expectancy;
    18. Known allergy or adverse reaction to sildenafil or any other ingredient in Revatio®;
    19. Known hereditary degenerative retinal disorders, such as retinitis pigmentosa, history of visual loss, untreated proliferative diabetic retinopathy, or history of non-arteritic ischemic optic neuropathy (NAION);
    20. Known priapism, hearing loss, vision changes, or epistaxis with any episodic use of PDE-5 inhibitor for erectile dysfunction;
    21. History of alcoholism or drug abuse, or prior symptoms of drug- or alcohol-related withdrawal;
    22. Participation in any other experimental studies involving other drug or non-drug therapies within 30 days before the current study begins and during study participation;
    23. Pregnant females; breastfeeding females; females of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after last dose of investigational product;
    24. Any severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the subject inappropriate for entry into this trial; or
    25. Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the trial.
    Los sujetos que presenten alguna de las siguientes situaciones no serán incluidos en el estudio:
    1. HAP como consecuencia de cualquier etiología que no sea las especificadas en los criterios de inclusión;
    2. Valvulopatía importante (es decir, > 2+) que no sea insuficiencia tricuspídea ni insuficiencia de la válvula pulmonar;
    3. Cardiopatía congénita a menos que cumplan los criterios de inclusión estipulados en la Sección ?4.1 o hipertensión pulmonar como consecuencia de tromboembolia;
    4. Septostomía auricular en los 6 meses anteriores a la aleatorización (se deberá retirar a los sujetos que necesiten someterse a este procedimiento durante el estudio);
    5. Infarto de miocardio, angina de pecho inestable, accidente cerebrovascular (ACV) o accidente isquémico transitorio (AIT) en los 6 meses anteriores a la aleatorización;
    6. Insuficiencia cardíaca aguda descompensada en los 3 meses anteriores a la aleatorización;
    7. Antecedentes de paro cardíaco, paro respiratorio, colapso hemodinámico, RCP, taquicardia ventricular, fibrilación ventricular o fibrilación auricular permanente;
    8. Antecedentes de embolia pulmonar verificada por gammagrafía de ventilación/perfusión, angiografía o tomografía axial computarizada helicoidal de tórax;
    9. Hipotensión definida como presión arterial sistólica < 90 mmHg o presión arterial diastólica < 50 mmHg después de permanecer sentado durante 5 minutos en la selección o el día 1;
    10. Tratamiento con inhibidores de la PDE-5 para la HAP (el uso ocasional anterior de inhibidores de la PDE-5 para la disfunción eréctil no inhabilita a un sujeto);
    11. Tratamiento con bosentán en el plazo de 3 meses de la aleatorización;
    12. Tratamiento actual con nitratos u óxido nítrico;
    13. Inicio de un tratamiento nuevo para la HAP <3 meses antes de la aleatorización o cambio en el tratamiento de base específico para la HAP en los 30 días anteriores a la aleatorización (es decir, ambrisentán y cualquier otro ARE que esté asequible durante la realización del estudio siempre y cuando el nuevo fármaco no sea un potente inductor o inhibidor del CYP3A [Appendix 1] que tenga una interacción farmacológica evidente desde el punto de vista clínico con el sildenafilo y/o prostanoides);
    14. Cambio en la clase de tratamiento de apoyo utilizado como tratamiento complementario de la HAP en los 30 días anteriores a la aleatorización (por ejemplo, oxígeno, antagonistas del calcio, digoxina, diuréticos);
    15. Tratamiento actual con inhibidores o inductores potentes del CYP3A4 (Appendix 1);
    16. Antecedentes de enfermedad pulmonar crónica/enfermedad pulmonar restrictiva (por ejemplo, enfermedad pulmonar obstructiva crónica [EPOC] o esclerodermia) con deterioro de la función pulmonar demostrado por una capacidad pulmonar total (CPT) pronosticada < 70%, o volumen espiratorio máximo en el primer segundo (VEMS) pronosticado < 60%. (Los sujetos con estos trastornos pulmonares deben hacerse pruebas de la función pulmonar antes de ingresar al estudio si no se las hicieron en los 12 meses anteriores);
    17. En el plazo de 5 años de la selección, antecedentes de neoplasias malignas (salvo carcinoma basocelular o carcinoma espinocelular de la piel tratados adecuadamente), virus de la inmunodeficiencia humana (VIH) o cualquier otra enfermedad que pueda limitar la esperanza de vida;
    18. Alergia o reacción adversa conocida al sildenafilo o a cualquier otro ingrediente de Revatio®;
    19. Trastornos retinianos degenerativos hereditarios conocidos, como por ejemplo retinitis pigmentaria, antecedentes de pérdida de la vista, retinopatía diabética proliferativa sin tratar o antecedentes de neuropatía óptica isquémica no arterítica (NOIANA);
    20. Acontecimientos conocidos de priapismo, pérdida de audición, alteraciones de la vista o epistaxis con cualquier uso ocasional de inhibidores de la PDE-5 para la disfunción eréctil;
    21. Antecedentes de alcoholismo o toxicomanía, o síntomas anteriores de abstinencia relacionada con fármacos o alcohol;
    22. Participación en cualquier otro estudio experimental que involucre otros tratamientos con o sin fármacos en los 30 días anteriores al comienzo del estudio actual y durante la participación en el estudio;
    23. Mujeres embarazadas; mujeres que amamantan; mujeres con capacidad para procrear y que no estén dispuestas o no puedan usar un método anticonceptivo de alta eficacia como se describe en este protocolo durante todo el estudio y durante por lo menos 28 días después de recibir la última dosis del producto en fase de investigación;
    24. Cualquier alteración de los resultados de análisis clínicos o afección psiquiátrica o médica grave, tanto crónica como aguda, que pudiera aumentar el riesgo que conlleva la participación en el ensayo o la administración del producto en fase de investigación o que pudiera interferir en la interpretación de los resultados del ensayo y que, a criterio del investigador, haría que el sujeto no fuera apto para ingresar en este estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoint:
    - Time to death (Mortality).
    Criterio principal de valoración de eficacia:
    - Tiempo hasta la muerte (mortalidad).
    E.5.1.1Timepoint(s) of evaluation of this end point
    NA
    NAP
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints:
    - Time to first event (Clinical Worsening); and
    - 6MWD at Months 6 and 12.
    Clinical worsening for the purpose of this study is defined as:
    - All-cause mortality;
    - Non-elective hospital stay for worsening PAH (including but not limited to right heart failure [RHF], initiation of IV prostanoids, lung transplantation, or septostomy); or
    - Disease progression (defined as a reduction from baseline in the 6MWD test by 15%, confirmed by 2nd test done within 2 weeks (cannot be performed on same day), and worsening functional class).
    Criterios secundarios de valoración de eficacia:
    - Tiempo hasta el primer evento (empeoramiento del cuadro clínico); y
    - PC6M a los 6 y 12 meses.
    El empeoramiento del cuadro clínico?8 a efectos de este estudio se define como:
    - Mortalidad por cualquier causa;
    - Estadía no optativa en el hospital por el empeoramiento de la HAP (que incluye, entre otras causas, insuficiencia cardíaca derecha [ICD], inicio de prostanoides IV, trasplante de pulmón o septostomía); o
    - Avance de la enfermedad (definido como la reducción desde el inicio en la PC6M en un 15%, confirmado por una segunda prueba realizada en el plazo de 2 semanas [no se puede hacer el mismo día] y empeoramiento de la clase funcional).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Time to first event, Months 6 and 12
    Tiempo hasta el primer evento, Mes 6 y 12
    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 Yes
    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 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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    3 different doses of the same product. Placebo is only used in order to maintain the blind.
    E.8.2.4Number of treatment arms in the trial3
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    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
    Bulgaria
    Canada
    Croatia
    Czech Republic
    Denmark
    Germany
    Greece
    Hong Kong
    Hungary
    Israel
    Italy
    Lithuania
    Malaysia
    Mexico
    Netherlands
    Poland
    Portugal
    Romania
    Russian Federation
    Serbia
    Singapore
    South Africa
    Spain
    Sweden
    Taiwan
    Thailand
    Ukraine
    United States
    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
    End of Trial in a Member State of the European Union is defined as the time at which it is deemed that sufficient subjects have been recruited and completed the study as stated in the regulatory application (CTA) in the Member State. Poor recruitment by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State.
    End of Trial in all other participating countries is defined as Last Subject Last Visit.
    En los Estados miembros de la UE se define la finalización del ensayo como el momento en que se ha convocado a la cantidad suficiente de sujetos y que estos han completado el estudio tal como se establece en la solicitud de registro (CTA).
    Un reclutamiento insuficiente en uno de los Estados miembros no constituye un motivo para la finalización prematura.
    La finalización del ensayo en todos los demás países participantes se define como la última visita del último sujeto.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 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: 360
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 69
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 300
    F.4.2.2In the whole clinical trial 429
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects who discontinue randomized study treatment for any reason will continue to be followed for survival at the time points specified in the schedule of activities for the duration of the study. All efforts should be made to follow all subjects for these data through standard of care visits or phone contact regardless of their participation in required study assessments.
    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 Decision2014-06-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-06-10
    P. End of Trial
    P.End of Trial StatusCompleted
    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
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