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    Summary
    EudraCT Number:2019-002817-21
    Sponsor's Protocol Code Number:AC-065A310
    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:2019-11-11
    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 number2019-002817-21
    A.3Full title of the trial
    A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Parallel-Group, Event-Driven, Group-Sequential Study with Open-Label Extension Period to Assess the Efficacy and Safety of Selexipag as Add-On Treatment to Standard of Care in Children Aged ≥2 to <18 years with Pulmonary Arterial Hypertension.
    Estudio aleatorizado, multicéntrico, doble ciego, controlado con placebo, de grupos paralelos, dirigido por eventos, de grupos secuenciales con un período de extensión abierto para evaluar la eficacia y seguridad de Selexipag añadido al tratamiento estándar en niños con edades comprendidas entre ≥ 2 y < 18 años con hipertensión arterial pulmonar (HAP).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to see if it is safe and helpful to add Selexipag to other PAH medication in children and adolescents.
    Un estudio para ver si es seguro y útil añadir Selexipag a otros medicamentos HAP en niños y adolescentes.
    A.3.2Name or abbreviated title of the trial where available
    SALTO
    SALTO
    A.4.1Sponsor's protocol code numberAC-065A310
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/123/2019
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorActelion Pharmaceuticals Ltd.
    B.1.3.4CountrySwitzerland
    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 supportActelion Pharmaceuticals Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen-Cilag International NV
    B.5.2Functional name of contact pointClinical Registry group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 CM
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31 71 5242166
    B.5.5Fax number+31 71 5242110
    B.5.6E-mailClinicalTrialsEU@its.jnj.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 Uptravi
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International NV
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSelexipag
    D.3.2Product code JNJ-67896049 (ACT-293987)
    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 INNSELEXIPAG
    D.3.9.2Current sponsor codeJNJ-67896049 (ACT-293987)
    D.3.9.4EV Substance CodeSUB130805
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSelexipag
    D.3.2Product code JNJ-67896049 (ACT-293987)
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Yes
    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 INNSELEXIPAG
    D.3.9.2Current sponsor codeJNJ-67896049 (ACT-293987)
    D.3.9.4EV Substance CodeSUB130805
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pulmonary Arterial Hypertension
    Hipertensión arterial pulmonar
    E.1.1.1Medical condition in easily understood language
    Pulmonary Arterial Hypertension (PAH) is a disease of the small pulmonary arteries that is characterized by vascular proliferation and remodeling.
    La hipertensión arterial pulmonar (HAP) es una enfermedad de las arterias pulmonares pequeñas que se caracteriza por la proliferación y remodelación vascular.
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10064911
    E.1.2Term Pulmonary arterial hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate whether the addition of selexipag to Standard of Care treatment delays disease progression in children with PAH in comparison to placebo.
    Evaluar si la adición de selexipag al tratamiento de referencia retrasa la progresión de la enfermedad en niños con hipertensión arterial pulmonar en comparación con el placebo.
    E.2.2Secondary objectives of the trial
    To assess the safety and tolerability of selexipag in children with PAH.
    To evaluate whether selexipag can delay hospitalization and death due to PAH worsening in children.
    To assess the trough plasma concentrations of selexipag and its active metabolite at steady-state in children with PAH.
    To explore the following safety and efficacy variables.
    To explore the Quality of Life (QoL).
    To explore the long-term safety, tolerability and efficacy of selexipag in children with PAH.
    Evaluar la seguridad y tolerabilidad de selexipag en niños con hipertensión arterial pulmonar.
    Evaluar si selexipag puede retrasar la hospitalización y la muerte a causa del empeoramiento de la hipertensión arterial pulmonar en niños.
    Evaluar las concentraciones plasmáticas mínimas de selexipag y su metabolito activo en estado de equilibrio en niños con hipertensión arterial pulmonar.
    Analizar las siguientes variables de seguridad y eficacia.
    Analizar la calidad de vida.
    Analizar la seguridad, la tolerabilidad y la eficacia a largo plazo de selexipag en niños con hipertensión arterial pulmonar.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Parent(s) (preferably both, if available, or as per local requirements, or their legally authorized representatives [LARs]) must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to allow the child to participate in the study. Assent is also required of children capable of understanding the nature of the study (typically 7 years of age and older) as described in Informed Consent Process in Section 10.4, Regulatory, Ethical, and Study Oversight Considerations.
    2. Male and female participants between ≥2 and <18 years of age weighing ≥9 kg at Randomization.
    3. PAH diagnosis confirmed by documented historical RHC performed at any time before participant’s screening, and characterized by:
    • mPAP ≥25 mmHg,
    AND
    • Pulmonary arterial wedge pressure (PAWP) ≤15 mmHg (in the absence of pulmonary vein obstruction and/or significant lung disease, PAWP can be replaced by left atrial pressure or, in absence of mitral stenosis, by left ventricular end diastolic pressure)
    AND
    • Indexed PVR index (PVRi) >3 Wood units × m2.
    4. PAH (WHO Group 1), including patients with Down syndrome, of the following etiologies:
    • Idiopathic PAH (IPAH).
    • Heritable PAH (HPAH).
    • PAH associated with congenital heart disease (PAH-aCHD):
    – PAH with coincidental CHD (ie, a small atrial septal defect, ventricular septal defect, or patent ductus arteriosus that does not itself account for the development of elevated PVR) and if approved by the BCAC, see Section 10.4).
    – Post-operative PAH (persisting / recurring/ developing ≥6 months after repair
    of CHD).
    • Drug or toxin-induced.
    • PAH associated with HIV.
    5. WHO FC II and III.
    6. Participants treated with at least 1 PAH-specific treatment, eg, an ERA and/or a PDE-5 inhibitor/soluble guanylate cyclase stimulator, provided that the treatment dose(s) has been stable for at least 3 months prior to screening.
    7. A female participant of childbearing potential (for a definition refer to section 10.6) is eligible only if the following apply:
     Has a negative highly sensitive serum pregnancy test (β-human chorionic gonadotropin) at screening and a negative urine pregnancy test at randomization.
     Agrees to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation.
     If sexually active, practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies until 30 days after last dose of study intervention. Examples of acceptable methods of contraception are located in Section 10.6. It is the responsibility of the investigator to ensure appropriate counselling, including consultation with a specialist (if needed), to the subject and/or parent(s) / LAR(s) on the acceptable method of contraception. To ensure compliance, the study personnel must remind female participants of childbearing potential who are sexually active and their parent(s) / LAR(s) at each visit to use the methods of contraception defined for this study. These reminders must be documented in the source documents.
    1.Los progenitores (preferiblemente ambos si están disponibles o según los requisitos locales, o su representante legal [RL]) deben firmar un FCI indicando que entienden el propósito del estudio y los procedimientos requeridos para este, y que están dispuestos a permitir que el niño participe en el estudio. También se requiere la aceptación de los niños capaces de comprender la naturaleza del estudio generalmente de 7 años o mayores,como se describe en el proceso de consentimiento informado en el apartado 10.4, Consideraciones reglamentarias, éticas y de supervisión del estudio
    2. Niños y niñas entre ≥2 y <18 años de edad con un peso ≥9 kg en el momento de la aleatorización.
    3.Diagnóstico de HAP confirmado mediante un CCD histórico documentado realizado en cualquier momento antes de la selección del participante y caracterizado por:
    •PAPm ≥25 mmHg,Y
    •Presión en cuña de la arteria pulmonar (PCAP) ≤15 mmHg (en ausencia de obstrucción de vena pulmonar o enfermedad pulmonar significativa, la PCAP puede sustituirse por presión auricular izquierda o, en ausencia de estenosis mitral, por presión diastólica final del ventrículo izquierdo) E
    •Índice de RVP (iRVP) incluido >3 unidades Wood x m2
    4.HAP (grupo 1 de la OMS), incluidos participantes con síndrome de Down, de las siguientes etiologías:
    •HAP idiopática (HAPi).
    •HAP hereditaria (HAPh).
    •HAP asociada a cardiopatía congénita (HAP-CCa):
    –HAP con CC casual (es decir, pequeña comunicación interauricular, comunicación interventricular o conducto arterial patente que no explica el desarrollo de RVP alta) y si el CVCI lo aprueba, consulte el apartado 10.4).
    –HAP posoperatoria (persistente/recurrente/en desarrollo ≥6 meses después de la reparación de la CC).
    •Inducida por fármacos o toxinas.
    •HAP asociada al VIH.
    5.CF II y III de la OMS
    6.Participantes tratados al menos con 1 tratamiento específico de la HAP, por ejemplo, un ARE o un inhibidor de FDE-5 o un estimulador soluble de guanilato ciclasa, siempre que las dosis de tratamiento hayan sido estables al menos durante 3 meses antes de la selección.
    7.Una mujer en edad fértil (para obtener una definición, consulte el apartado 10.6) solo se considera elegible si se cumple lo siguiente:
    Da negativo en una prueba de embarazo en suero de alta sensibilidad ( gonadotropina coriónica humana) en la fase de selección y en una prueba de embarazo en orina en la fase de aleatorización.
    Acepta someterse a pruebas mensuales de embarazo en orina durante el estudio y por lo menos hasta 30 días después de la discontinuación del tratamiento del estudio.
    Si es sexualmente activa, utiliza un método anticonceptivo muy eficaz en consonancia con las normativas locales respecto al uso de métodos anticonceptivos para pacientes que participan en estudios clínicos hasta 30 días después de la última dosis del tratamiento del estudio. Se ofrecen ejemplos de métodos anticonceptivos aceptables en el apartado 10.6. Es responsabilidad del investigador garantizar el asesoramiento adecuado, incluida la consulta con un especialista (si es necesario), al participante o progenitores o representantes legales sobre el método anticonceptivo aceptable. Para garantizar el cumplimiento, el personal del estudio debe recordar a las participantes en edad fértil que sean sexualmente activas y a sus progenitores o representantes legales en cada visita que utilicen métodos anticonceptivos definidos para este estudio. Estos recordatorios deben documentarse en los documentos originales.
    E.4Principal exclusion criteria
    Etiology
    1. PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease, and/or pulmonary capillary hemangiomatosis.
    2. PAH associated with Eisenmenger syndrome.
    3. Moderate to large left-to-right shuntsa.
    4. Cyanotic congenital cardiac lesions such as transposition of the great arteries, truncus arteriosus, univentricular heart, or pulmonary atresia with ventricular septal defect, as well as subjects with Fontan-palliation.
    5. Participants with PH due to lung disease and/or hypoxia. For participants with Down syndrome, exclusion of lung disease and hypoxia causing PH must be documented (eg, normal oxygen saturation in absence of history of lung disease, computed tomography scan, polysomnography, lung function tests).

    Treatment and intervention
    6. Previous exposure to Uptravi® (selexipag).
    7. Treatment with prostacyclin (epoprostenol) or prostacyclin analogsa (ie, treprostinil, iloprost, beraprost) within 2 months prior to randomization or scheduled to receive any of these treatments during the study.
    8. Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before the planned first dose of study intervention or is currently enrolled in an investigational study
    9. Treatment with strong and moderate inhibitors of CYP2C8 (eg, gemfibrozil, clopidogrel, deferasirox, teriflunomide) from 2 weeks prior to randomization until the last dose of study intervention +3 days
    10. Treatment with inhibitors of UGT1A3 and UGT2B7 (valproic acid, probenecid, and fluconazole) from 2 weeks prior to randomization until the last dose of study intervention + 3 days
    11. Any PAH-related surgical intervention planned, or subjects listed for organ transplantation related to PAH.

    Medical history and co-morbidities
    12. Known concomitant life-threatening disease with a life expectancy <12 months
    13. History or current suspicion of intussusception or ileus or gastrointestinal obstruction, per the investigator’s judgment
    14. Uncontrolled thyroid disease, per the investigator’s judgment
    15. Hemoglobin or hematocrit <75% of the lower limit of normal range
    16. Known severe or moderate hepatic impairment, ie, Child-Pugh Class B or C
    17. Clinical signs of hypotension that, in the investigator’s judgment, would preclude initiation of a PAH-specific therapy
    18. Severe renal insufficiency (estimated creatinine clearance <30 mL/min or serum creatinine >221 μmol/L)
    19 Severe coronary heart disease or unstable angina as assessed by the investigator
    20. Myocardial infarction within the last 6 months prior to enrollment
    21. Decompensated cardiac failure if not under close supervision
    22. Severe arrhythmias as assessed by the investigator
    23. Cerebrovascular events (eg, transient ischemic attack, stroke) within the last 3 months prior to enrollment
    24. Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to PH

    Pregnancy and breastfeeding
    25. Pregnant, planning to become pregnant, or lactating

    Other categories
    26. Known allergies, hypersensitivity, or intolerance to selexipag or its excipients (Selexipag IB)
    27. Any known factor or disease that might interfere with treatment compliance, study conduct, or interpretation of the results, such as drug or alcohol dependence or psychiatric disease
    28. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the child (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
    1.HAP debida a hipertensión portal, esquistosomiasis, enfermedad venooclusiva pulmonar o hemangiomatosis capilar pulmonar.
    2.HAP asociada al síndrome de Eisenmenger.
    3.Derivaciones de izquierda a derecha de moderadas a grandes .
    4.Lesiones cardíacas congénitas cianóticas como transposición de las arterias grandes, tronco arterial, corazón univentricular o atresia pulmonar con defecto de la comunicación interventricular, así como participantes con paliación de Fontan.
    5.Participantes con HP debida a enfermedad pulmonar o hipoxia. En los participantes con síndrome de Down, se debe documentar la exclusión de enfermedad pulmonar e hipoxia que causan la HP (p. ej., saturación de oxígeno normal en ausencia de antecedentes de enfermedad pulmonar, tomografía computarizada, polisomnografía, pruebas de función pulmonar).

    Tratamiento y fármacos
    6.Exposición previa a Uptravi® (selexipag).
    7.Tratamiento con prostaciclina (epoprostenol) o análogos de prostaciclina (es decir, treprostinil, iloprost, beraprost) en los 2 meses previos a la aleatorización o programado para recibir cualquiera de estos tratamientos durante el estudio.
    8.Haber recibido un fármaco en investigación (incluidas vacunas experimentales) o haber utilizado un dispositivo médico invasivo en investigación en las 4 semanas anteriores a la primera dosis programada del tratamiento del estudio, o estar actualmente reclutado en un estudio de investigación.
    9.Tratamiento con inhibidores potentes y moderados de CYP2C8 (p. ej., gemfibrozilo, clopidogrel, deferasirox, teriflunomida) desde 2 semanas antes de la aleatorización hasta la última dosis del tratamiento del estudio +3 días.
    10.Tratamiento con inhibidores de UGT1A3 y UGT2B7 (ácido valproico, probenecid y fluconazol) desde 2 semanas antes de la aleatorización hasta la última dosis del tratamiento del estudio +3 días.
    11.Cualquier intervención quirúrgica prevista relacionada con la HAP o participantes en lista de espera para un trasplante de órganos relacionado con la HAP.

    Historia clínica y enfermedades concomitantes
    12.Enfermedad concomitante terminal conocida con una esperanza de vida <12 meses.
    13.Antecedentes o sospecha actual de invaginación intestinal o íleo u obstrucción gastrointestinal, según el criterio del investigador.
    14.Enfermedad tiroidea no controlada, según el criterio del investigador.
    15.Hemoglobina o hematocrito <75 % del límite inferior de la normalidad.
    16.Insuficiencia hepática grave o moderada conocida, es decir, clasificación B o C de Child-Pugh (consulte el apartado 10.12).
    17.Signos clínicos de hipotensión que, en opinión del investigador, impedirían el inicio de un tratamiento específico de la HAP.
    18.Insuficiencia renal grave (aclaramiento de creatinina estimado <30 ml/min o creatinina sérica >221 µmol/l).
    19.Cardiopatía coronaria grave o angina inestable determinadas por el investigador.
    20.Infarto de miocardio en los 6 meses anteriores al reclutamiento.
    21.Insuficiencia cardíaca descompensada no supervisada estrechamente.
    22.Arritmias graves determinadas por el investigador.
    23.Acontecimientos cerebrovasculares (p. ej., accidente isquémico transitorio, accidente cerebrovascular) en los 3 meses anteriores al reclutamiento.
    24.Defectos valvulares congénitos o adquiridos con trastornos de la función miocárdica de trascendencia clínica no relacionados con la HP.
    Embarazo y lactancia
    25.Mujeres embarazadas, que tengan intención de quedarse embarazadas o que estén amamantando.

    Otras categorías
    26.Alergias, hipersensibilidad o intolerancia conocidas a selexipag o a sus excipientes (MI de selexipag).
    27.Cualquier enfermedad o factor conocido que puedan interferir con el cumplimiento del tratamiento, la realización del estudio o la interpretación de los resultados (por ejemplo, dependencia de drogas o alcohol, o enfermedad psiquiátrica).
    28.Cualquier enfermedad para la cual, en opinión del investigador, la participación no redundaría en el mejor interés del niño (por ejemplo, podría poner en peligro su bienestar) o que podría evitar, limitar o confundir las evaluaciones especificadas en el protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    Time to disease progression from randomization up to 7 days after study treatment discontinuation.
    Tiempo hasta la progresión de la enfermedad desde la aleatorización hasta 7 días después de la discontinuación del tratamiento del estudio
    E.5.1.1Timepoint(s) of evaluation of this end point
    Randomization up to 7 days after EOT.
    Aleatorización hasta los 7 días después del fin del tratamiento.
    E.5.2Secondary end point(s)
    • Treatment-emergent adverse events and serious adverse events.
    • Adverse events leading to premature discontinuation of study treatment
    • Treatment-emergent change in vital signs (systolic and diastolic arterial blood pressure and pulse rate) and body weight from baseline to all assessed time points
    • Growth: Treatment-emergent change in body weight and height from baseline to all assessed time points
    • Sexual maturation (Tanner stage) from baseline to all assessed time points up to 3 days after study treatment discontinuation
    • Treatment-emergent electrocardiogram abnormalities.
    • Treatment-emergent marked laboratory abnormalities at each time point of assessment.
    • Treatment emergent change from baseline in thyroid stimulating hormone over time.
    • Treatment emergent change in selected laboratory variables from baseline to all assessed time points.
    • Time to first Clinical Event Committee-confirmed hospitalization or death due to pulmonary arterial hypertension occurring from Randomization until 7 days after study treatment discontinuation.
    • Trough plasma concentration at steady-state of Selexipag and its metabolite ACT-333679 collected during the maintenance period.

    Exploratory
    • Time to death (all causes) occurring between Randomization and the Analysis Visit for each Analysis.
    • Time to first Clinical Event Committee-confirmed death due to pulmonary arterial hypertension occurring from randomization until 7 days after study treatment discontinuation.
    • Time to Clinical Event Committee-confirmed disease progression up to the Analysis Visit for each Analysis.
    • World Health Organization functional class III (yes/no) at each time point of assessment up to 7 days after study treatment discontinuation.
    • Change in World Health Organization functional class from baseline/enrollment to each time point of assessment up to 7 days after study treatment discontinuation.
    • Change from baseline to each time point of assessment in exercise capacity up to 7 days after study treatment discontinuation as measured by the 6-minute walk distance in children ≥6 years of age who are developmentally able to understand and perform the test.
    • Change in physical activity (measured by accelerometry) from baseline to 1 year (48 weeks) after Randomization.
    • Change in Panama functional class from baseline to each time point of assessment up to 7 days after study treatment discontinuation.
    • Percent of baseline in plasma N-terminal pro-brain natriuretic peptide at each time point of assessment up to 7 days after study treatment discontinuation.
    • Change from baseline in echocardiographic variables (imaging and Doppler evaluation) such as right ventricular systolic pressure, tricuspid annular plane systolic excursion, etc, at each time point of assessment up to 7 days after study treatment discontinuation.
    • Time to disease progression from randomization up 7 days after study treatment discontinuation defined as:
    1. All-cause death.
    2. Time to non-planned pulmonary arterial hypertension related hospitalization.
    3. Time to pulmonary arterial hypertension related deterioration identified by at least one of the following parameters:
    i. increase in World Health Organization functional class,
    ii. deterioration in exercise testing (15% decrease from baseline of 6-minute walk distance),
    iii. signs or symptoms of right-sided heart failure.
    • Quality of Life as measured by the PedsQL™ 4.0 Generic Core Scales Short Form.Quality of Life as measured by the disease-specific PedsQL™ 3.0 Cardiac Module using the “heart problems and treatment” component only.
    • Quality of Life as measured by the PedsQL™ Multidimensional Fatigue Scale standard version using the “general fatigue” component only.
    • Palatability of the study intervention at Day 1, Week 12, and End of Treatment, assessed using a 5-point facial hedonic scale.
    • Acceptability of the study intervention at Day 1, Week 12, and End of Treatment, as assessed through a 3-point categorical scale as to whether the child swallowed the medication.
    •AA relacionados con el tratamiento y AA graves.
    •AA que provoquen la discontinuación del tratamiento del estudio.
    •Cambio derivado del tratamiento en las constantes vitales (presión arterial sistólica y diastólica, y frecuencia de pulso) y en el peso corporal desde el momento de referencia hasta todos los puntos temporales evaluados.
    •Crecimiento: cambio derivado del tratamiento en el peso corporal y la estatura desde el momento de referencia hasta todos los puntos temporales evaluados.
    •Maduración sexual (etapa de Tanner) desde el momento de referencia hasta todos los puntos temporales evaluados hasta 3 días después de la discontinuación del tratamiento del estudio.
    •Anomalías electrocardiográficas derivadas del tratamiento.
    •Anomalías analíticas evidentes derivadas del tratamiento en cada punto temporal de evaluación.
    •Cambio derivado del tratamiento desde el momento de referencia en la hormona estimulante de la tiroides a lo largo del tiempo.
    •Cambio derivado del tratamiento en variables analíticas seleccionadas desde el momento de referencia hasta todos los puntos temporales evaluados.
    Una anomalía o acontecimiento derivados del tratamiento se asocian temporalmente al uso del tratamiento del estudio, ya se consideren o no relacionados con el tratamiento del estudio según el investigador.

    Eficacia
    •Cambio en la CF modificada de la New York Heart Association/OMS desde el momento de referencia/reclutamiento hasta cada punto temporal de evaluación hasta 7 días después de la discontinuación del tratamiento del estudio.
    •Cambio en la CF de Panamá desde el momento de referencia hasta cada punto temporal de evaluación hasta 7 días después de la discontinuación del tratamiento del estudio.
    •Tiempo hasta la progresión de la enfermedad (evaluada por el investigador) desde la aleatorización hasta 7 días después de la discontinuación del tratamiento del estudio
    E.5.2.1Timepoint(s) of evaluation of this end point
    Disease progression is defined as the first occurrence of either of the following components:
    − Death (all causes)
    − Atrial septostomy or Potts’ anastomosis, or registration on lung transplant list
    − Hospitalization due to worsening pulmonary arterial hypertensiona
    − Clinical worsening of pulmonary arterial hypertension.
    •Tiempo hasta la progresión de la enfermedad desde la aleatorización hasta 7 días después de la discontinuación del tratamiento del estudio. Un Comité de acontecimientos clínicos no conocedor de la asignación decidirá sobre la progresión de la enfermedad que se define como la primera aparición de cualquiera de los siguientes componentes:
    -Muerte (por cualquier causa)
    -Septostomía auricular o anastomosis de Potts, o registro en la lista para un trasplante de pulmón
    -Hospitalización por empeoramiento de la hipertensión arterial pulmonar
    -Empeoramiento clínico de la hipertensión arterial pulmonar definido como:
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic 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 Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    Tolerabilidad
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Event-Driven and Group-Sequential. Open label extension.
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA41
    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
    Belarus
    Belgium
    Brazil
    Bulgaria
    Canada
    China
    Colombia
    Denmark
    Finland
    France
    Germany
    Hungary
    Israel
    Italy
    Korea, Republic of
    Lithuania
    Malaysia
    Mexico
    Netherlands
    Poland
    Portugal
    Romania
    Russian Federation
    Serbia
    Spain
    Sweden
    Switzerland
    Taiwan
    Thailand
    Turkey
    Ukraine
    United States
    Vietnam
    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
    The end of study is considered as the last scheduled study assessment shown in the Schedule of Activities for the last participant in the study (LVLS).
    El final del estudio se considerará la última evaluación programada que se muestra en el Programa de Actividades para el último participante en el estudio (última visita, último paciente)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 237
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 60
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 177
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 41
    F.4.2.2In the whole clinical trial 237
    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)
    Safety Follow-up Period: starts on the day after the last dose of study intervention (after either the double-blind or the open-label study intervention) and ends 30 days thereafter with a safety telephone call. Participants who do not plan to enter the open-label extension (OLEP) period will have this Safety Follow-up Period 30 days after the Analysis Visit for each Analysis. In the OLEP this call constitutes the end of study contact.
    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 Decision2020-01-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-20
    P. End of Trial
    P.End of Trial StatusOngoing
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