E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Eisenmenger Syndrome |
Síndrome de Eisenmenger |
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E.1.1.1 | Medical condition in easily understood language |
Condition caused by a defect in the heart that affects blood flow between the heart and the lungs |
Estado causado por un defecto en el corazón que afecta al flujo sanguineo entre el corazón y los pulmones |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10058554 |
E.1.2 | Term | Eisenmenger's syndrome |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 is to demonstrate that macitentan improves exercise capacity in comparison with placebo in subjects with Eisenmenger Syndrome |
El objetivo primario es demostrar que Macitentan mejora la capacidad de esfuerzo en comparación con placebo en sujetos con síndrome de Eisenmenger |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate the effects of macitentan in comparison with placebo on: - WHO functional class - Dyspnea (assessed by the Borg dyspnea index), - Quality of Life (QoL; assessed by the Short-Form 36 [SF-36] questionnaire). |
Los objetivos secundarios son evaluar los efectos de Macitentan en comparación con placebo sobre: ? Clase funcional de la Organización Mundial de la Salud (WHO). ? Disnea (evaluada mediante el índice de disnea de Borg). ? Calidad de vida (QoL; evaluada mediante el Cuestionario abreviado de salud de 36 apartados (SF-36)). |
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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 |
"Hemodynamic sub-study", version 1 dated 09 October 2012:
Exploratory objective to evaluate the effects of macitentan in comparison with placebo on hemodynamic parameters (in a sub-set of subjects). |
"Sub-estudio hemodinámico", versión 1 de fecha 09 Octubre 2012: Objetivo exploratorio evaluar los efectos de macitentan en comparación con placebo sobre parámetros hemodinámicos (en un subgrupo de pacientes). |
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E.3 | Principal inclusion criteria |
- Subjects: ? not participating in the hemodynamic sub-study: males or females ? 12 and ? 70 years of age. ? participating in the hemodynamic sub-study: males or females ? 18 and ? 70 years of age.
- Subjects with confirmed ES (European Society of Cardiology [ESC] and the European Respiratory Society [ERS] guidelines): ? Established by echocardiography as: o Isolated ASD > 2 cm in diameter, o or isolated VSD > 1 cm in diameter, o or presence of both ASD and VSD (with either VSD ? 1 cm in diameter and ASD > 2 cm in diameter, or VSD > 1 cm in diameter and ASD ? 2 cm in diameter, or VSD > 1 cm in diameter and ASD > 2 cm in diameter), o and right to left shunt or bi-directional shunt with prevalent right to left direction. ? Unoperated, or previously palliated surgically for defects mentioned above (incomplete closure). ? Resting peripheral arterial oxygen saturation (SaO2) ? 90% and >70% (pulse oximetry, room air).
- Cardiac catheterization measurements must show the following: ? Mean resting pulmonary arterial pressure (mPAP) > 25 mmHg, ? Pulmonary capillary wedge pressure (PCWP) or mean left atrial pressure (LAP) or left ventricular end diastolic pressure (LVED) ? 15 mmHg, ? Pulmonary vascular resistance (PVR) ? 800 dyn?s/cm5 or ? 10 Wood units.
- Subjects with WHO functional class ? II.
- Subjects able to perform the 6-minute walk test (6MWT) with a minimum distance of 50 m and a maximum distance of 450 m. |
- Sujetos: ? Que no participen en el subestudio hemodinámico: varones o mujeres con una edad ? 12 y ? 70 años. ? Que participen en el subestudio hemodinámico: varones o mujeres con una edad ? 18 y ? 70 años. - Sujetos con ES confirmado (directrices de la Sociedad Europea de Cardiología [ESC] y la Sociedad Europea de Neumología [ERS]): ? Confirmado mediante ecocardiografía como: o ASD aislada > 2 cm de diámetro o o VSD aislada > 1 cm de diámetro o o presencia de ASD y VSD (con VSD ? 1 cm de diámetro y ASD > 2 cm de diámetro o VSD > 1 cm de diámetro y ASD ? 2 cm de diámetro o VSD > 1 cm de diámetro y ASD > 2 cm de diámetro) o y cortocircuito derecha-izquierda o cortocircuito bidireccional con dirección derecha-izquierda predominante. ? No operados o sometidos a cirugía paliativa previa por los defectos mencionados anteriormente (cierre incompleto). ? Saturación arterial periférica de oxígeno (SaO2) en reposo ? 90% y > 70% (pulsioximetría, aire ambiente). ? Las determinaciones del cateterismo cardíaco deberán indicar todo lo siguiente: ? Presión media en la arteria pulmonar (mPAP) en reposo > 25 mm Hg. ? Presión de enclavamiento capilar pulmonar (PCWP), o presión media en la aurícula izquierda (LAP) o presión telediastólica del ventrículo izquierdo (LVED) ? 15 mm Hg, ? Resistencia vascular pulmonar (PVR) ? 800 din?s/cm5 o ? 10 unidades Wood.
- Sujetos con una clase funcional de la WHO ? II.
- Sujetos capaces de realizar la prueba de marcha de 6 minutos (6MWT) con una distancia mínima de 50 m y una distancia máxima de 450 m. |
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E.4 | Principal exclusion criteria |
- Pulmonary arterial hypertension (PAH) not fulfilling the criteria of ES as described in inclusion criterion 3 (e.g., complex cardiac defects, single ventricle, and patent ductus arteriosus).
- Known moderate-to-severe restrictive (i.e., total lung capacity [TLC] < 60% of predicted value) or obstructive lung disease (i.e., forced expiratory volume in one second [FEV1] < 80 % of predicted, with FEV1 / forced vital capacity [FVC] < 70%).
- Down Syndrome.
- Treatment with phosphodiesterase-5 (PDE-5) inhibitors or prostanoids within 1 month prior to Randomization.
- Treatment with endothelin receptor antagonists (ERAs) within 1 month prior to Randomization.
- Subjects who initiated diuretics within 1 week prior to Randomization or subjects whose diuretic treatment has not been stable within 1 week prior to Randomization.
- Subjects being considered for an organ transplant. |
- Hipertensión arterial pulmonar (PAH) que no cumple los criterios de ES descritos en el criterio de inclusión 3 (por ejemplo, defectos cardíacos complejos, ventrículo único y conducto arterioso permeable).
- 2. Neumopatía restrictiva moderada a grave (es decir, capacidad pulmonar total [TLC] < 60% del valor teórico) o neumopatía obstructiva moderada a grave (es decir, volumen espiratorio forzado en el primer segundo [FEV1] < 80% del valor teórico, con FEV1/capacidad vital forzada [FVC] < 70%).
- Síndrome de Down.
- Tratamiento con inhibidores de la fosfodiesterasa-5 (PDE-5) o prostanoides en el mes previo a la aleatorización.
- Tratamiento con antagonistas de los receptores de la endotelina (ERA) en el mes previo a la aleatorización.
- Sujetos que han empezado a recibir diuréticos en la semana previa a la aleatorización o cuyo tratamiento diurético no se ha mantenido estable en la semana previa a la aleatorización.
- Sujetos en los que esté planteándose el trasplante de un órgano. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline to Week 16 in exercise capacity, as measured by the 6MWD. |
Variación entre el momento basal y la semana 16 de la capacidad de esfuerzo, medida mediante la 6MWD. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Baseline - Week 16 |
- Momento basal - Semana 16 |
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E.5.2 | Secondary end point(s) |
Change from baseline to Week 16 in: ? WHO functional class, ? Dyspnea (assessed by the Borg dyspnea index), ? QoL (assessed by the SF-36 questionnaire). |
Variación entre el momento basal y la semana 16 de: ?Clase funcional de la WHO. ? Disnea (evaluada mediante el índice de disnea de Borg). ? QoL (evaluada mediante el cuestionario SF-36). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Baseline - Week 16 |
- Momento basal - Semana 16 |
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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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability. Hemodynamic for sub-study only |
Tolerabilidad. Hemodinámica sólo para sub-estudio. |
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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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
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 | Yes |
E.8.2.3 | Other | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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 |
Austria |
Belgium |
Bulgaria |
Canada |
Chile |
China |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Malaysia |
Mexico |
Netherlands |
Philippines |
Poland |
Portugal |
Russian Federation |
Serbia |
South Africa |
Spain |
Taiwan |
Turkey |
United Kingdom |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |