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    Summary
    EudraCT Number:2019-003309-88
    Sponsor's Protocol Code Number:ROR-PH-302
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-02-21
    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 number2019-003309-88
    A.3Full title of the trial
    A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Ralinepag to Evaluate Safety and Effects on Exercise Capacity Assessed by Cardiopulmonary Exercise Testing in Subjects with World Health Organization Group 1 Pulmonary Hypertension Who Recently Initiated Therapy (ADVANCE Capacity)
    Estudio en fase III, aleatorizado, con doble enmascaramiento y controlado con placebo de ralinepag para evaluar la seguridad y los efectos en la capacidad de ejercicio evaluada mediante pruebas de ejercicio cardiopulmonar en sujetos con hipertensión pulmonar según el grupo 1 de la Organización Mundial de la Salud que iniciaron recientemente tratamiento (ADVANCE Capacity)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized double blind, placebo controlled study in pulmonary arterial hypertension using cardiopulmonary exercise testing.
    Estudio aleatorizado, doble ciego, controlado con placebo en hipertensión arterial pulmonar utilizando pruebas de ejercicio cardiopulmonar.
    A.3.2Name or abbreviated title of the trial where available
    ADVANCE Capacity
    A.4.1Sponsor's protocol code numberROR-PH-302
    A.5.4Other Identifiers
    Name:IND NumberNumber:109021
    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 SponsorUnited Therapeutics Corporation
    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 supportUnited Therapeutics Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUnited Therapeutics Corporation
    B.5.2Functional name of contact pointRegulatory Department
    B.5.3 Address:
    B.5.3.1Street Address55 T.W. Alexander Drive, PO Box 14186
    B.5.3.2Town/ cityResearch Triangle Park
    B.5.3.3Post codeNC 27709
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1919485-8350
    B.5.5Fax number+1919485-8352
    B.5.6E-mailinfo1@unither.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/3/18/2130
    D.3 Description of the IMP
    D.3.1Product nameRalinepag
    D.3.2Product code APD811
    D.3.4Pharmaceutical form Prolonged-release 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 INNRALINEPAG
    D.3.9.1CAS number 1187856-49-0
    D.3.9.2Current sponsor codeAPD811
    D.3.9.3Other descriptive nameAR392830
    D.3.9.4EV Substance CodeSUB193414
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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/3/18/2130
    D.3 Description of the IMP
    D.3.1Product nameRalinepag
    D.3.2Product code APD811
    D.3.4Pharmaceutical form Prolonged-release 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 INNRALINEPAG
    D.3.9.1CAS number 1187856-49-0
    D.3.9.2Current sponsor codeAPD811
    D.3.9.3Other descriptive nameAR392830
    D.3.9.4EV Substance CodeSUB193414
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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/3/18/2130
    D.3 Description of the IMP
    D.3.1Product nameRalinepag
    D.3.2Product code APD811
    D.3.4Pharmaceutical form Prolonged-release 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 INNRALINEPAG
    D.3.9.1CAS number 1187856-49-0
    D.3.9.2Current sponsor codeAPD811
    D.3.9.3Other descriptive nameAR392830
    D.3.9.4EV Substance CodeSUB193414
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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 (PAH)
    hipertensión arterial pulmonar (HAP)
    E.1.1.1Medical condition in easily understood language
    high lung blood pressure
    hipertensión 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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10077731
    E.1.2Term Pulmonary hypertension WHO functional class I
    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 evaluate the effects of ralinepag therapy on exercise capacity as assessed by change in peak oxygen consumption (VO2) derived from cardiopulmonary exercise testing (CPET) after 28 weeks of treatment
    Evaluar los efectos de la terapia con ralinepag sobre la capacidad de ejercicio según lo evaluado por el cambio en el consumo máximo de oxígeno (VO2) derivado de las pruebas de ejercicio cardiopulmonar (CPET) después de 28 semanas de tratamiento.
    E.2.2Secondary objectives of the trial
    To evaluate the effects of ralinepag on:
    1. N-terminal pro b-type natriuretic peptide (NT-proBNP)
    2. Minute ventilation (VE)/carbon dioxide output (VCO2) slope
    3. WHO/New York Heart Association (NYHA) Functional Class (FC)
    4. Health-related quality of life (HRQoL) measured by the Short Form (36) Health Survey (SF-36)
    5. Time to first all-cause nonelective hospitalization
    6. Safety and tolerability
    Note: Other protocol defined exploratory objectives may apply.
    Evaluar los efectos de ralinepag en:
    1. Péptido natriurético de tipo B pro-terminal N (NT-proBNP)
    2. Pendiente de ventilación minuto (VE) / salida de dióxido de carbono (VCO2)
    3. Clase funcional (FC) de la OMS / New York Heart Association (NYHA)
    4. Calidad de vida relacionada con la salud (CVRS) medida por la Encuesta de salud de formulario corto (36) (SF-36)
    5. Tiempo hasta la primera hospitalización no selectiva por cualquier causa
    6. Seguridad y tolerabilidad.
    Nota: Pueden aplicarse otros objetivos exploratorios definidos por el protocolo.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Optional evaluation of proteomics, metabolomics, transcriptomics, and pharmacogenetic analysis:
    For subjects who agree to participate in the optional proteomics, metabolomics, and transcriptomics analyses, blood samples will be collected at Baseline, the Week 28 Visit, or the Study Drug Termination Visit; for subjects who agree to participate in the optional genetic analysis, a blood sample will be collected at Baseline.
    Evaluación opcional de proteómica, metabolómica, transcriptómica y análisis farmacogenético:
    Para los sujetos que aceptan participar en los análisis opcionales de proteómica, metabolómica y transcriptómica, se recolectarán muestras de sangre en la visita de referencia, en la semana 28 o en la visita de finalización del estudio farmacológico; Para los sujetos que aceptan participar en el análisis genético opcional, se recolectará una muestra de sangre al inicio del estudio.
    E.3Principal inclusion criteria
    Each subject must meet ALL of the following inclusion criteria to be eligible for enrollment into the study:
    1) Evidence of a personally signed and dated Informed Consent Form (ICF) indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any study-related procedures.
    2) At least 18 years of age at the time of consent.
    3) Primary diagnosis of PAH classified by one of the following subgroups:
    a. Idiopathic pulmonary arterial hypertension (IPAH)
    b. Heritable pulmonary arterial hypertension (HPAH)
    c. Drugs or toxins induced based on prior exposure to drugs, chemicals, or toxins, such as fenfluramine derivatives, other anorexigens, toxic rapeseed oil, or L-tryptophan
    d. PAH associated with:
    i. Connective tissue disease (CTD)
    ii. Human immunodeficiency virus (HIV) infection
    iii. Congenital systemic-pulmonary shunt (must have undergone surgical correction at least 1 year prior to Screening) and have no, or a clinically insignificant, shunt fraction (1.0≤pulmonary-systemic flow ratio [QP/QS] ≤1.5)
    4. Has had a diagnostic right heart catheterization (RHC) performed within 1 year of Screening (or during Screening if one is not available) that is consistent with the diagnosis of PAH, meeting all of the following criteria:
    a) Pulmonary artery pressure mean (PAPm) >20 mmHg (at rest)
    b) Pulmonary artery wedge pressure (PAWP) ≤15 mmHg (If PAWP cannot be reliably attained, then left ventricular end diastolic pressure [LVEDP] ≤15 mmHg)
    c) Pulmonary vascular resistance (PVR) ≥3 Wood units or ≥240 dynes/sec/cm5
    If more than 1 RHC was performed within 1 year of Screening, the most recent RHC that includes parameters sufficient to evaluate the above criteria must be used for this assessment.
    5) Has WHO/NYHA FC 2 to 3 symptoms at Baseline.
    6) Must have initiated first PAH-specific oral therapy with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 inhibitor (PDE5-I) or a soluble guanylate cyclase (sGC) stimulator within 9 months prior to Screening, and be on a stable dose(s), defined as no change in dose or regimen for at least 30 days prior to Screening. Subjects may be on a stable dose of either a PDE5-I or a sGC stimulator, not both.
    a) If the subject’s disease-specific PAH therapy does not include a PDE5-I, the use of PDE5-I as needed for erectile dysfunction (ED), up to 3 doses per week, is permitted. The subject should not have taken a dose within 48 hours of Baseline.
    7) Has a 6MWD of ≥150 meters during Screening.
    8) Has a VE/VCO2 slope ≥38 during the Screening CPET, as assessed by the CPET core lab.
    9) Has a peak VO2 of ≥10 to <18 mL·kg-1·min-1 during the Screening CPET, as assessed by the CPET core lab.
    10) If the subject is taking concomitant medications that may affect PAH (ie, calcium channel blockers, digoxin, diuretics, beta blockers, Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or L-arginine), the subject must be on a stable dose for at least 30 days prior to the Baseline Visit and the dosage maintained throughout the study. The exception is that the dose of diuretics should remain stable for at least the 10 days prior to Baseline.
    11. Both male and female subjects agree to use a highly effective method of birth control throughout the entire study period from informed consent through to the Week 28 Visit/28-day Follow-up Visit, if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in a conception process (ie, actively attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) during the study and for 4 weeks after the last dose of study drug.
    Cada sujeto debe cumplir TODOS los siguientes criterios de inclusión para ser elegible para la inscripción en el estudio:
    1) Evidencia de un Formulario de consentimiento informado (ICF) firmado y fechado personalmente que indique que el sujeto ha sido informado de todos los aspectos pertinentes del estudio antes del inicio de cualquier procedimiento relacionado con el estudio.
    2) Al menos 18 años de edad en el momento del consentimiento.
    3) Diagnóstico primario de HAP clasificada por uno de los siguientes subgrupos:
    a. Hipertensión arterial pulmonar idiopática (IPAH)
    si. Hipertensión arterial pulmonar hereditaria (HPAH)
    C. Drogas o toxinas inducidas en base a la exposición previa a drogas, químicos o toxinas, como derivados de fenfluramina, otros anorexígenos, aceite de colza tóxico o L-triptófano
    re. HAP asociada a:
    yo. Enfermedad del tejido conectivo (CTD)
    ii. Infección por el virus de la inmunodeficiencia humana (VIH)
    iii) Derivación sistémica-pulmonar congénita (debe haberse sometido a corrección quirúrgica al menos 1 año antes de la detección) y no tener, o una fracción de derivación clínicamente insignificante (relación de flujo sistémico pulmonar 1.0≤ [QP / QS] ≤1.5)
    4. Se le realizó un diagnóstico de cateterismo del corazón derecho (RHC) dentro de 1 año de la detección (o durante la detección si no hay uno disponible) que sea consistente con el diagnóstico de HAP, cumpliendo con todos los siguientes criterios:
    a) Presión media de la arteria pulmonar (PAPm)> 20 mmHg (en reposo)
    b) Presión de la cuña de la arteria pulmonar (PAWP) ≤15 mmHg (Si no se puede lograr la PAWP de manera confiable, entonces la presión diastólica del extremo ventricular izquierdo [LVEDP] ≤15 mmHg)
    c) Resistencia vascular pulmonar (PVR) ≥3 unidades de madera o ≥240 dinas / seg / cm5
    Si se realizó más de 1 RHC dentro de 1 año después de la detección, se debe usar el RHC más reciente que incluye parámetros suficientes para evaluar los criterios anteriores para esta evaluación.
    5) Tiene síntomas de OMS / NYHA FC 2 a 3 al inicio del estudio.
    6) Debe haber iniciado la primera terapia oral específica de HAP con un antagonista del receptor de endotelina (ERA) y / o un inhibidor de la fosfodiesterasa tipo 5 (PDE5-I) o un estimulador de guanilato ciclasa soluble (sGC) dentro de los 9 meses previos a la detección, y estar en una dosis estable, definida como la ausencia de cambios en la dosis o el régimen durante al menos 30 días antes de la detección. Los sujetos pueden estar en una dosis estable de un PDE5-I o un estimulador sGC, no ambos.
    a) Si la terapia de HAP específica de la enfermedad del sujeto no incluye un PDE5-I, se permite el uso de PDE5-I según sea necesario para la disfunción eréctil (DE), hasta 3 dosis por semana. El sujeto no debería haber tomado una dosis dentro de las 48 horas posteriores al inicio.
    7) Tiene un 6MWD de ≥150 metros durante la detección.
    8) Tiene una pendiente VE / VCO2 ≥38 durante el CPET de detección, según lo evaluado por el laboratorio central de CPET.
    9) Tiene un VO2 máximo de ≥10 a <18 ml · kg-1 · min-1 durante el CPET de detección, según lo evaluado por el laboratorio central de CPET.
    10) Si el sujeto está tomando medicamentos concomitantes que pueden afectar la HAP (es decir, bloqueadores de los canales de calcio, digoxina, diuréticos, bloqueadores beta, inhibidores de la enzima convertidora de angiotensina, bloqueadores del receptor de angiotensina II o L-arginina), el sujeto debe estar en un dosis estable durante al menos 30 días antes de la visita de referencia y la dosis mantenida durante todo el estudio. La excepción es que la dosis de diuréticos debe permanecer estable durante al menos los 10 días anteriores a la línea de base.
    11. Tanto los hombres como las mujeres acuerdan utilizar un método anticonceptivo altamente efectivo durante todo el período de estudio desde el consentimiento informado hasta la visita de la semana 28 / visita de seguimiento de 28 días, si existe la posibilidad de concepción. Los sujetos masculinos y femeninos elegibles también deben aceptar no participar en un proceso de concepción (es decir, intentar activamente quedar embarazadas o embarazarse, donación de esperma, fertilización in vitro) durante el estudio y durante 4 semanas después de la última dosis del fármaco del estudio.
    E.4Principal exclusion criteria
    Subjects must not meet ANY of the following exclusion criteria to be eligible for enrollment into the study:
    1) subjects with known HIV-associated PAH, a cluster designation 4 (CD4+) T-cell count <200/mm3 at Screening.
    ]2) Has 3 or more of the following left ventricular disease/dysfunction risk factors:
    a) Body mass index (BMI) ≥30 kg/m2
    b) History of systemic hypertension
    c) Diabetes mellitus - any type
    d) Historical evidence of significant coronary artery disease established by any 1 of the following:
    i) History of myocardial infarction or percutaneous coronary intervention or angiographic evidence of coronary artery disease (>50% stenosis in at least 1 coronary artery)
    ii) Positive stress test with imaging
    iii) Previous coronary artery bypass graft
    iv) Angina
    e) Chronic atrial fibrillation
    3) Current unstable angina.
    4) Symptomatic coronary disease and/or myocardial infarction within past 6 months.
    5) Current symptomatic aortic or mitral valve disease.
    6) Has evidence of more than mild lung disease on pulmonary function tests (PFTs) performed within 1 year prior to, or during, Screening. Subjects with any of the following criteria will be excluded:
    a. Forced expiratory volume in 1 second (FEV1) <60% predicted; or
    b. Total lung capacity (TLC) <60% predicted
    7) Has evidence of thromboembolic disease as determined by ventilation-perfusion (V/Q) lung scan or local standard of care diagnostic evaluation at or after diagnosis of PAH.
    8) Current diagnosis of uncontrolled sleep apnea in the clinical opinion of the Investigator.
    9) Requires use of supplemental oxygen during CPET procedures.
    10) Respiratory exchange ratio (RER) <1.0 at Screening CPET, as determined by the CPET core laboratory.
    11) Acute non-cardiac disorder that may affect exercise performance (eg, infection, renal failure, thyrotoxicosis).
    12) Male subjects with a corrected QT interval using Fridericia’s formula (QTcF) >450 msec and female subjects with QTcF >470 msec on electrocardiogram (ECG) recorded in triplicate at Screening in subjects without evidence of intraventricular conduction delay (IVCD). In presence of IVCD, subjects will be excluded if QTcF is >500 msec for both males and females.
    13) Severe chronic liver disease (ie, Child-Pugh C), portal hypertension, cirrhosis, or complications of cirrhosis/portal hypertension (eg, history of variceal hemorrhage, encephalopathy).
    14) hepatitis B virus (HBV) or hepatitis C virus (HCV).
    15) Subjects with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times the upper limit of normal (ULN) or total bilirubin ≥2 × ULN at Screening.
    16) Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL or requiring dialysis at Screening.
    17) Hemoglobin concentration <9 g/dL at Screening.
    18) Subjects treated with an intravenous (IV) or subcutaneous (SC) prostacyclin pathway agent (eg, epoprostenol, treprostinil, or iloprost) at any time prior to Baseline (use in vasoreactive testing is permitted).
    19) Subjects treated with an inhaled or oral prostacyclin pathway agent (iloprost, treprostinil, beraprost, or selexipag) that was stopped for a safety or tolerability issue.
    • If a subject discontinued for other reasons, the subject is eligible if the subject has been off therapy and stable for 90 days prior to Baseline.
    20) Subject has pulmonary veno-occlusive disease.
    21) Malignancy diagnosed and/or treated within 5 years of Screening, with the exception of localized non-metastatic basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix excised with curative intent.
    22. Subject tests positive for amphetamine, cocaine, methamphetamine, methylenedioxymethamphetamine, or phencyclidine in urine drug screen performed at Screening or has a recent history (6 months) of alcohol or drug abuse.
    23) Initiation or discontinuation of a cardio-pulmonary rehabilitation program based upon exercise within 90 days prior to Screening and/or planned during study participation.
    24) Prior participation in any study of ralinepag or participation in another interventional clinical study within 30 days prior to Screening. Concurrent participation in registry or observational studies is allowed, as long as the subject can fulfill all other entry criteria and comply with all study procedures.
    25) Any reason that, in the opinion of the Investigator, precludes the subject from participating in the study that may increase the risk associated with study participation or that would confound study analysis (eg, right-to-left shunt detected during CPET) or impair study participation or cooperation.
    26) Known hypersensitivity to ralinepag or any of the excipients.
    27) Life expectancy <12 months.
    28. Women who are pregnant, lactating, or breast-feeding.
    1) sujetos con HAP asociada al VIH conocida, un grupo de designación 4 (CD4 +) recuento de células T <200 / mm3 en el cribado.
    2) Tiene 3 o más de los siguientes factores de riesgo de enfermedad / disfunción del ventrículo izquierdo: a) (IMC) ≥30 kg / m2 b) Historia de hipertensión sistémica c) Diabetes mellitus - cualquier tipo d) Evidencia histórica de enfermedad coronaria significativa establecida por cualquiera de los siguientes: i) infarto de miocardio o intervención coronaria percutánea o de enfermedad arterial coronaria (> 50% de estenosis en al menos 1 arteria coronaria) ii) Prueba de esfuerzo positiva con imágenes iii) Injerto de derivación de arteria coronaria previa iv) Angina e ) Fibrilación auricular crónica 3) Angina inestable actual. 4) Enfermedad coronaria sintomática y / o infarto de miocardio en los últimos 6 meses. 5) Enfermedad valvular aórtica o mitral sintomática actual. 6) Evidencia de una enfermedad pulmonar más que leve en las pruebas de función pulmonar (PFT) realizadas dentro de 1 año antes o durante la detección. Los temas que serán excluidos:
    a. Volumen espiratorio forzado en 1 segundo (FEV1) <60% previsto; o b. Capacidad pulmonar total (TLC) <60% pronosticada 7) Evidencia de enfermedad tromboembólica según lo determinado por la exploración pulmonar por perfusión de ventilación (V / Q) o la evaluación diagnóstica local estándar de atención en o después del diagnóstico de HAP. 8) Apnea del sueño no controlada en la opinión clínica del investigador. 9) Requiere el uso de oxígeno suplementario durante los procedimientos de CPET.
    10) Relación de intercambio respiratorio (RER) <1.0 en la detección de CPET, según lo determinado por el laboratorio central de CPET.
    11) Trastorno no cardíaco agudo que puede afectar el rendimiento del ejercicio (p. Ej., Infección, insuficiencia renal, tirotoxicosis). 12) Hombres con un intervalo QT corregido utilizando la fórmula de Fridericia (QTcF)> 450 ms y mujeres con QTcF> 470 ms en electrocardiograma (ECG) registrado por triplicado en la detección en sujetos sin evidencia de retraso de la conducción intraventricular (IVCD). En presencia de IVCD, los sujetos serán excluidos si QTcF es> 500 ms para hombres y mujeres. 13) Enfermedad hepática crónica grave (es decir, Child-Pugh C), hipertensión portal, cirrosis o complicaciones de cirrosis / hipertensión portal (p. Ej., Antecedentes de hemorragia varicosa, encefalopatía). 14) virus de la hepatitis B (VHB) o el virus de la hepatitis C (VHC).
    15) Sujetos con alanina aminotransferasa (ALT) o aspartato aminotransferasa (AST) ≥3 veces el límite superior de la normalidad (ULN) o bilirrubina total ≥2 × ULN en el cribado. 16) Insuficiencia renal crónica definida por creatinina sérica> 2.5 mg / dL o que requiere diálisis en el cribado. 17) Concentración de hemoglobina <9 g / dL en el cribado.
    18) Sujetos tratados con un agente de la vía de prostaciclina intravenosa (IV) o subcutánea (SC) (p. Ej., Epoprostenol, treprostinil o iloprost) en cualquier momento antes de la línea de base (se permite el uso en pruebas vasoreactivas). 19) Sujetos tratados con un agente de vía de prostaciclina inhalado u oral (iloprost, treprostinil, beraprost o selexipag) que se detuvo por un problema de seguridad o tolerabilidad.
    • Si un sujeto se descontinuó por otras razones, el sujeto es elegible si el sujeto ha estado fuera de la terapia y estable ) durante 90 días antes del inicio. 20) El sujeto tiene enfermedad venooclusiva pulmonar. 21) Malignidad diagnosticada y / o tratada dentro de los 5 años posteriores a la detección, con la excepción del carcinoma de células basales o de células escamosas no metastásico localizado de la piel o el carcinoma in situ de cuello uterino extirpado con intención curativa. 22. El sujeto da positivo por anfetamina, cocaína, metanfetamina, metilendioximetanfetamina o fenciclidina en el análisis de drogas en orina realizado en Screening o tiene un historial reciente (6 meses) de abuso de alcohol o drogas. 23) Inicio o interrupción de un programa de rehabilitación cardiopulmonar basado en el ejercicio dentro de los 90 días previos a la detección y / o planeado durante la participación en el estudio. 24) Participación previa en cualquier estudio de ralinepag u estudio clínico intervencionista dentro de los 30 días previos a la detección. Se permite la participación concurrente en el registro o en estudios observacionales, siempre que el sujeto pueda cumplir con todos los demás criterios de ingreso y cumplir con todos los procedimientos del estudio.
    25) Cualquier razón que, en opinión del investigador, impida que el sujeto participe en el estudio o perjudicar la participación o cooperación en el estudio. 26) Hipersensibilidad conocida a ralinepag o cualquiera de los excipientes. 27) Esperanza de vida <12 meses. 28. Mujeres embarazadas, lactantes o en periodo de lactancia.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is the change from Baseline in peak VO2 after 28 weeks of treatment with study drug.
    El punto final primario del estudio es el cambio desde el valor basal en el VO2 máximo después de 28 semanas de tratamiento con el fármaco del estudio.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Through the study.
    A través del estudio
    E.5.2Secondary end point(s)
    The following secondary endpoints will be analyzed in hierarchical order:
    • Change from Baseline at Week 28 in NT-proBNP: NT-proBNP with log transformation will be analyzed in the ITT population using mixed-effect model repeated measures (MMRM) analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline NT-proBNP as a covariate
    • Change from Baseline at Week 28 in VE/VCO2 slope: VE/VCO2 slope will be analyzed in the mITT population and repeated in the ITT population using ANCOVA with a model that includes treatment and the stratification factors as factors and Baseline VE/VCO2 slope as a covariate.
    • Change in SF-36 scores from Baseline to Week 28: the component and domain scores will be analyzed in the ITT population using MMRM analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline component/domain score as a covariate.
    • Time to first all-cause nonelective hospitalization in randomized subjects during the study period will be analyzed in the ITT population using Cox proportional hazard regression model that includes treatment and the stratification factors.
    Los siguientes puntos finales secundarios se analizarán en orden jerárquico:
    • Cambio desde la línea de base en la semana 28 en NT-proBNP: NT-proBNP con transformación logarítmica se analizará en la población de ITT utilizando el análisis de medidas repetidas del modelo de efectos mixtos (MMRM) con tratamiento, los factores de estratificación, la semana y el tratamiento por- interacción semanal como factores y NT-proBNP basal como covariable
    • Cambio desde la línea de base en la semana 28 en la pendiente VE / VCO2: la pendiente VE / VCO2 se analizará en la población mITT y se repetirá en la población ITT utilizando ANCOVA con un modelo que incluye el tratamiento y los factores de estratificación como factores y la pendiente basal VE / VCO2 como una covariable
    • Cambio en los puntajes SF-36 de la línea de base a la semana 28: los puntajes de componentes y dominios se analizarán en la población de ITT utilizando el análisis MMRM con el tratamiento, los factores de estratificación, la semana y la interacción tratamiento por semana como factores y componentes de línea de base / puntaje de dominio como una covariable.
    • El tiempo hasta la primera hospitalización no selectiva por todas las causas en sujetos aleatorizados durante el período de estudio se analizará en la población ITT utilizando el modelo de regresión de riesgos proporcionales de Cox que incluye el tratamiento y los factores de estratificación.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the study.
    A lo largo del estudio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Optional evaluation of proteomics, metabolomics, transcriptomics, and genetics
    Evaluación opcional de proteómica, metabolómica, transcriptómica y genética.
    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 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 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 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 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    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
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Czech Republic
    Germany
    Italy
    Poland
    Spain
    United Kingdom
    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
    LVLS
    Último sujeto, última visita
    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: 155
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 38
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 193
    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)
    All subjects who complete the study on study drug through Week 28 will have the option to receive ralinepag in an open-label extension (OLE) study
    Todos los sujetos que completen el estudio sobre el fármaco del estudio hasta la semana 28 tendrán la opción de recibir ralinepag en un estudio de extensión abierta (OLE)
    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 Decision2020-06-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-31
    P. End of Trial
    P.End of Trial StatusOngoing
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