E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary arterial hypertension |
Hipertensión arterial pulmonar |
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E.1.1.1 | Medical condition in easily understood language |
Pulmonary Arterial Hypertension is a condition in which the pressure in the blood vessels going to the lungs (the pulmonary arteries) is higher than normal |
Hipertensión arterial pulmonar es la codicion en la cual la presion de los vasos sanguineos que van a los pulmones ( arterias pulmonares) es mas alta de lo normal. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to evaluate macitentan in comparison to Standard of Care (SoC) with regard to delaying disease progression in children with PAH. |
El objetivo principal del estudio consiste en evaluar macitentán en comparación con el tratamiento de referencia (TR) en lo que respecta al retraso de la progresión de la enfermedad en niños con hipertensión arterial pulmonar (HAP). |
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E.2.2 | Secondary objectives of the trial |
To assess safety and tolerability of macitentan in children with PAH. To assess PK of macitentan in children with PAH. |
Evaluar la seguridad y la tolerabilidad de macitentán en niños con HAP. Evaluar la farmacocinética (FC) de macitentán en niños con HAP. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic (PK) Substudy. Optional for up to 40 subjects. The analysis of the PK sub-study will be used to select the appropriate daily dose in subjects below 2 years of age. |
La participación en el subestudio de farmacocinética será opcional para un máximo de 40 pacientes. El análisis del subestudio de farmacocinética se utilizará para seleccionar la dosis diaria apropiada para los sujetos menores de dos años |
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E.3 | Principal inclusion criteria |
1. Signed informed consent by the parent(s) or legally designated representative AND assent from developmentally capable children prior to initiation of any study-mandated procedure. 2. Males or females between maior an equal to 2 years and minor to 18 years of age. 3. Subjects with body weight ≥ 10 kg at randomization. 4. PAH diagnosis, confirmed by historical RHC (mPAP ≥ 25 mmHg, and PAWP ≤ 15 mmHg, and PVRi > 3 WUxm2). 5. PAH belonging to the Nice 2013 Updated Classification Group 1 (including subjects with Down syndrome) and of following etiologies: • iPAH • hPAH • PAH associated with CHD • Drug or toxin induced PAH • PAH associated with HIV • PAH-aCTD 6. WHO FC I to III. 7. Females of childbearing potential must have a negative pregnancy test at Screening and at Baseline, and must agree to undertake monthly pregnancy tests, and to use a reliable method of contraception (if sexually active) up to EOS. |
1.Consentimiento informado firmado por los padres o el representante legal Y asentimiento de los niños capaces desde el punto de vista del desarrollo antes de realizar ningún procedimiento exigido por el estudio. 2.Sujetos de cualquier sexo con una edad mayor o igual a 2 y menor a 18 años. 3.Sujetos con un peso corporal mayor oigual a 10 kg en el momento de la aleatorización. 4.Diagnóstico de HAP menor or igaul a 12 meses antes de la aleatorización, confirmada mediante un cateterismo cardíaco derecho histórico (CCD; caracterizado por una presión arterial pulmonar media mayor o igual a 25 mm Hg, una presión de enclavamiento arterial pulmonar menor o igual a 15 mm Hg y una resistencia vascular pulmonar[iRVP] mayor a 3 unidades Wood x m2) 5.HAP perteneciente al grupo 1 de la clasificación de Niza actualizada en 2013 (incluido síndrome de Down) y de las siguientes etiologías: •HAP idiopática (HAPi). •HAP hereditaria (HAPh). •HAP asociada a cardiopatía congénita (CC) •HAP inducida por drogas o toxinas. •HAP asociada al VIH. •HAP asociada a enfermedad del tejido conjuntivo (HAP ETC). 6.Clase funcional I a III de la OMS. 8. Las pacientes en edad fértil deberán tener una prueba de embarazo negativa en la selección y el momento basal, así como comprometerse a someterse a pruebas de embarazo mensuales y a utilizar un método anticonceptivo fiable (en caso de ser sexualmente activas) hasta el FDE |
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E.4 | Principal exclusion criteria |
1. Subjects with PAH due to portal hypertension, schistosomiasis, or with pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn. 2. Subjects with PAH associated with Eisenmenger syndrome, or with moderate tolarge left-to right shunts 3. Subjects receiving a combination of > 2 PAH-specific treatments at randomization. 4. Treatment with i.v. or s.c. prostanoids within 4 weeks before randomization, unless given for vasoreactivity testing. 5. Hemoglobin or hematocrit <75% of the lower limit of normal range 6. Serum AST and/or ALT > 3 times the upper limit of normal range' 7. Pregnancy (including family planning) or breastfeeding. 8. Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol |
1.Sujetos con HAP debida a hipertensión portal, esquistosomiasis, enfermedad venooclusiva pulmonary/o hemangiomatosis capilar pulmonar y hipertensión pulmonar persistente del neonato. Tratamiento e intervención 2.Sujetos con HAP asociada a sindrome de Eisenmenger o con cortocircuitos izquierda-derecha abiertos de moderados a grandes. 3. Sujetos que estén recibiendo una combinación de más de dos tratamientos específicos para la HAP en el momento de la aleatorización. 4.Tratamiento con prostanoides IV o SC en las cuatro semanas previas a la aleatorización, a menos que se hayan administrado para estudiar la vasorreactividad 5. Hemoglobina o hematocritomenor a 75% del límite inferior del intervalo normal. 6.Concentración de aspartato aminotransferasa y/o alanina aminotransferasa en suero mayor a 3 veces el límite superior del intervalo normal. 7.Embarazo (incluida planificación familiar) o lactancia 8.Abuso de drogas o sustancias psicoactivas o cualquier trastorno que, en opinión del investigador, pueda impedir el cumplimiento del protocolo o del tratamiento del estudio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the time to the first of the following CEC-confirmed disease progression events occurring between randomization and EOS: • Death (all causes) • Atrial septostomy or Potts’ anastomosis, or registration on lung transplant list • Hospitalization due to worsening PAH • Clinical worsening of PAH |
El criterio de valoración principal de la eficacia será el tiempo transcurrido hasta que se produzca el primero de los siguientes acontecimientos de progresión de la enfermedad confirmados por el CAC entre la aleatorización y el final del estudio: •Muerte (por cualquier causa). •Septostomía auricular o anastomosis de Potts, o inscripción en la lista de espera para un trasplante de pulmón. •Hospitalización por empeoramiento de la HAP§. •Empeoramiento clínico de la HAP |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Between randomization and End-of-Study (EOS) |
Entre la aleatorización y el fin de estudio |
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E.5.2 | Secondary end point(s) |
The secondary endpoints are analyzed in the following hierarchical order: • Time to first CEC-confirmed hospitalization for PAH occurring between randomization and EOS. • Time to CEC-confirmed death due to PAH occurring between randomization and EOS. • Time to death (all causes) occurring between randomization and Study Closure. |
Los criterios de valoración secundarios serán: •Tiempo transcurrido hasta la primera hospitalización por HAP confirmada por el CAC que se produzca entre la aleatorización y el final del estudio. •Tiempo transcurrido hasta la muerte por HAP confirmada por el CAC que se produzca entre la aleatorización y el final del estudio. •Tiempo transcurrido hasta la muerte (por cualquier causa) que se produzca entre la aleatorización y el cierre del estudio. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Between randomization and End-of-Study (EOS) |
Entre la aleatorización y el fin de estudio |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 56 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Austria |
Bulgaria |
Canada |
China |
France |
Germany |
Hungary |
Israel |
Korea, Republic of |
Mexico |
Philippines |
Poland |
Portugal |
Russian Federation |
South Africa |
Spain |
Thailand |
Ukraine |
United States |
Vietnam |
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E.8.7 | Trial 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
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The study is considered completed when the last subject completes the study (i.e. last EOS visit or last safety follow-up contact, whichever occurs last) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |