E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary arterial hypertension
Hipertensión arterial pulmonar |
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 |
La hipertensión arterial pulmonar es una condición en la cual la presión a los pulmones (arterias pulmonares) es más 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 | 14.1 |
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 |
- To evaluate the psychometric characteristics of reliability and construct validity of the French, Italian and Spanish versions of the PAH-SYMPACT?
- To evaluate the ability of the French, Italian and Spanish versions of the PAH-SYMPACT? to detect change |
Evaluar las características psicométricas de fiabilidad y validez del constructo de las versiones en francés, italiano y español del PAH SYMPACT™.
Evaluar la capacidad para detectar cambio de las versiones en francés, italiano y español del PAH SYMPACT™.
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E.2.2 | Secondary objectives of the trial |
To assess the safety of macitentan in patients with PAH |
Valorar la seguridad de macitentan en pacientes con hipertensión arterial pulmonar (HAP). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed informed consent prior to initiation of any study-mandated procedure.
2. Patients with symptomatic PAH in WHO Functional Class (FC) II or III.
3. Patients with PAH belonging to one of the following subgroups of the Dana Point Clinical Classification Group 1:
a. Idiopathic, or,
b. Heritable, or,
c. Drug or toxin induced, or,
d. Associated with one of the following:
i. Connective tissue disease,
ii. Congenital heart disease with simple systemic-to-pulmonary shunt at least 1 year after surgical repair,
iii. HIV infection.
4. Documented hemodynamic diagnosis of PAH by right heart catheterization ? performed at any time prior to Screening showing:
a. Resting mean pulmonary arterial pressure (mPAP) ? 25 mmHg and,
b. Resting pulmonary vascular resistance (PVR) > 240 dyn·s·cm-5 and,
c. Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ? 15 mmHg.
5. 6-minute walk distance (6MWD) ? 150 m at Screening.
6. Able to fluently speak and read the local language.
7. Men or women aged 18?80; women of childbearing potential must:
a. have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline and agree to perform monthly serum pregnancy tests, and,
b. agree to use two reliable methods of contraception in parallel, from Screening Visit 1 until 1 month after study drug discontinuation. |
1. Consentimiento informado firmado en anterioridad a la iniciación de cualquier procedimiento exigido por el estudio.
2. Pacientes con HAP sintomática en la Clase funcional (CF) II o III de la OMS.
3. Pacientes con HAP que pertenezcan a uno de los siguientes subgrupos del Grupo 1 de la clasificación clínica Dana Point:
a. Idiopática, o,
b. Hereditaria, o,
c. Inducida por medicamentos o toxinas, o,
d. Asociada con alguno de lo siguiente:
i. Enfermedad del tejido conectivo,
ii. Cardiopatía congénita con cortocircuito sistémico pulmonar simple al menos 1 año tras la reparación quirúrgica,
iii. Infección por VIH.
4. Diagnosis hemodinámica documentada de HAP por cateterismo cardíaco derecho – realizada en cualquier momento antes de la Selección que muestre:
a. Presión arterial pulmonar media en reposo (PAPm) ≥ 25 mmHg y,
b. Resistencia vascular pulmonar en reposo (RVP) > 240 dyn•s•cm5 y,
c. Presión capilar pulmonar en cuña (PCPC) o presión diastólica final del ventrículo izquierdo (PDFVI) ≤ 15 mmHg.
5. Distancia caminada en 6 minutos (DC6M) ≥ 150 m en la selección.
6. Capaz de hablar con fluidez y leer el idioma local.
7. Hombres o mujeres de 18–80 años de edad; las mujeres en edad fértil deben:
a. presentar una prueba sérica de embarazo negativa en la selección y una prueba de embarazo negativa en orina en el inicio, así como estar de acuerdo en realizar pruebas séricas de embarazo mensualmente, y,
b. aceptar utilizar en paralelo dos métodos anticonceptivos fiables, a partir de la visita 1 de selección hasta 1 mes después de la discontinuación del medicamento del estudio.
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E.4 | Principal exclusion criteria |
1. Known moderate-to-severe obstructive lung disease (i.e., forced expiratory volume in one second [FEV1] < 80% of predicted, with FEV1 / forced vital capacity [FVC] < 70%) or known significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung disease, emphysema).
2. Known moderate-to-severe restrictive lung disease (i.e., total lung capacity [TLC] < 60% of predicted value).
3. Hemoglobin < 100g/L at Screening.
4. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 X the upper limit of the normal range (ULN) at Screening.
5. Patients undergoing dialysis.
6. Systolic blood pressure (SBP) < 90 mmHg at Screening.
7. Body weight < 40 kg at Screening.
8. Known concomitant life-threatening diseases with a life expectancy of < 12 months.
9. Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to Visit 2, or scheduled to receive any of these compounds, other than macitentan, during the trial.
10. Treatment with intravenous or subcutaneous prostacyclin or prostacyclin analogs within 3 months prior to Visit 2, or scheduled to receive any of these compounds during the trial.
11. Treatment with soluble guanylate cyclase stimulator (riociguat) within 3 months prior to Visit 2, or scheduled to receive riociguat during the trial.
12. Patients who changed the dose of or discontinued phosphodiesterase type-5 inhibitors (PDE5i), inhaled prostacyclin analogues, or calcium channel blockers within 3 months prior to Visit 2.
13. Initiation of diuretics within 1 week prior to the Baseline period.
14. Patients on oral diuretics in whom the dose has not been stable for at least 1 week prior to the Baseline period.
15. Treatment with cytochrome P450 (CYP) 3A inducers within 4 weeks prior to Visit 2.
16. Recently started (< 8 weeks prior to Visit 2) or planned cardio-pulmonary rehabilitation program based on exercise.
17. Females who are lactating or pregnant (positive Screening or Baseline pregnancy test) or plan to become pregnant during the study.
18. Known hypersensitivity to macitentan or its excipients or drugs of the same class.
19. Treatment with another investigational drug within 3 months prior to Visit 2.
20. 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. |
1. Enfermedad pulmonar obstructiva conocida entre moderada y grave (es decir, con un volumen espiratorio forzado en un segundo [VEF1] < 80 % del previsto, con VEF1 / capacidad vital forzada [CVF] < 70 %) o enfermedad pulmonar crónica significativa conocida, con diagnosis por escanografía de tórax (p. ej., enfermedad pulmonar intersticial, enfisema).
2. Enfermedad pulmonar restrictiva conocida entre moderada y grave (es decir, capacidad pulmonar total [CPT] < 60 % del valor previsto).
3. Hemoglobina < 100 g/l en la selección.
4. Aspartato aminotransferasa (AST) y/o alanino aminotransferasa (ALT) séricas > 3 el límite superior de la normalidad (LSN) en la selección.
5. Pacientes sometidos a diálisis.
6. Presión arterial sistólica (PAS) < 90 mmHg en la selección.
7. Peso corporal < 40 kg en la selección.
8. Enfermedades potencialmente mortales concomitantes conocidas con una expectativa de vida de < 12 meses.
9. Tratamiento con antagonistas de receptores de endotelina (ERA) en el transcurso de los 3 meses previos a la visita 2, o programado para recibir cualquiera de estos compuestos, aparte de macitentan, durante el ensayo.
10. Tratamiento con prostaciclina o sus análogos, por vía intravenosa o subcutánea, en el transcurso de los 3 meses previos a la visita 2, o programado para recibir cualquiera de estos compuestos durante el ensayo.
11. Tratamiento con estimulador de la guanilato ciclasa soluble (riociguat) en el transcurso de los 3 meses previos a la visita 2, o programado para recibir riociguat durante el ensayo.
12. Pacientes que cambiaron, o discontinuaron, la dosis de inhibidores de fosfodiesterasa tipo 5 (PDE5i), análogos de prostaciclina inhalados o antagonistas de los canales de calcio en el transcurso de los 3 meses previos a la visita 2.
13. Iniciación de diuréticos en el transcurso de 1 semana previa al período inicial.
14. Pacientes que reciben diuréticos orales cuya dosis no haya sido estable durante al menos 1 semana previa al período inicial.
15. Tratamiento con inductores del citocromo P450 (CYP) 3A en el transcurso de las 4 semanas previas a la visita 2.
16. Haber iniciado recientemente (< 8 semanas previas a la visita 2) o planificado un programa de rehabilitación cardiopulmonar basado en el ejercicio.
17. Mujeres durante la lactancia o embarazadas (prueba de embarazo positiva en la selección o el inicio) o con plan de quedarse embarazadas durante el estudio.
18. Hipersensibilidad conocida a macitentan o sus excipientes o medicamentos de la misma clase.
19. Tratamiento con otro medicamento en investigación en el transcurso de los 3 meses previos a la visita 2.
20. Cualquier factor o enfermedad conocido que podría interferir con el cumplimiento del tratamiento, la realización del estudio o la interpretación de los resultados tales como alcoholismo o drogodependencia, o trastorno psiquiátrico.
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E.5 End points |
E.5.1 | Primary end point(s) |
The study psychometrically validates the French, Italian and Spanish versions of the PAH-SYMPACT? in patients with PAH |
El estudio valida psicométricamente las versiones en francés, italiano y español del PAH-SYMPACT™ en pacientes con HAP |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At screening, twice during baseline, twice during treatment. |
En screening, dos veves en la visita basal, dos veces durante el tratamiento |
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E.5.2 | Secondary end point(s) |
Safety endpoints
- Treatment-emergent adverse events (AEs).
- AEs leading to premature discontinuation of study drug.
- Treatment-emergent serious adverse events (SAEs).
- Change from Baseline to Week 16 in vital signs, i.e., supine SBP, DBP, and HR.
- Proportion of patients with treatment-emergent ALT and/or AST abnormality (> 3, > 5, and > 8 X ULN) associated or not with total bilirubin > 2 X ULN, up to EOT.
- Proportion of patients with treatment-emergent hemoglobin abnormality (? 100 g/L, and ? 80 g/L), up to EOT. |
• Acontecimientos adversos (AA) emergentes del tratamiento.
• AA que resultan en la discontinuación prematura del medicamento del estudio.
• Acontecimientos adversos graves (AAG) emergentes del tratamiento.
• Cambio desde el inicio hasta la semana 16 en las constantes vitales, es decir, PAS, PAD y FC en posición supina.
• Proporción de pacientes con anomalías de ALT y/o AST emergentes del tratamiento (> 3, > 5 y > 8 LSN) asociadas o no con bilirrubina total > 2 LSN, hasta el fin del tratamiento (EOT).
• Proporción de pacientes con anomalías de hemoglobina emergentes del tratamiento (≤ 100 g/l y ≤ 80 g/l), hasta el EOT.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Visits 1, 2, 3, 4 and 5 |
visitas 1,2,3,4 y 5 |
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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 | No |
E.6.5 | Efficacy | No |
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 |
Psychometric characteristics of reliability and construct validity of the French, Italian and Spanish versions of the PAH-SYMPACT? |
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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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 14 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |