E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Resistant Hypertension |
hipertensión arterial resistente |
|
E.1.1.1 | Medical condition in easily understood language |
Difficult to control high blood pressure despite treatment with at least 3 other anti-hypertensive medications |
Dificultad para controlar la elevada tensión sanguínea a pesar del tratamiento con 3 o más antihipertensivos |
|
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 | LLT |
E.1.2 | Classification code | 10020783 |
E.1.2 | Term | Hypertension not adequately controlled |
E.1.2 | System Organ Class | 100000004866 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate the blood pressure (BP) lowering effect of aprocitentan when added to standard of care in true resistant hypertension (RHT) subjects. |
Demostrar la capacidad de aprocitentán para reducir la presión arterial (PA) cuando se añade al tratamiento estándar en sujetos con hipertensión resistente (HR) real |
|
E.2.2 | Secondary objectives of the trial |
- To demonstrate that the effect of aprocitentan on BP is durable when added to standard of care in true RHT subjects.
- To evaluate the long-term safety and tolerability of aprocitentan in true RHT subjects during 48 weeks of treatment. |
- Demostrar que los efectos de aprocitentán sobre la PA son duraderos cuando este se añade al tratamiento estándar en sujetos con HR real. - Evaluar la seguridad y la tolerabilidad a largo plazo de aprocitentán en sujetos con HR real durante 48 semanas de tratamiento. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Screening visit: Signed and dated ICF prior to any study-mandated procedure; Male and female subjects; 18 years (or year of country specific majority) or older; Historical documentation in the subject’s medical records on uncontrolled BP despite at least 3 background antihypertensive medications within 1 year before screening visit; Treated with at least 3 antihypertensive therapies of different pharmacological classes including a diuretic for at least 4 weeks before the screening visit (Visit 1); Mean SiSBP ≥ 140 mmHg measured by AOBPM; Women of childbearing potential are eligible only if the following applies; Negative pregnancy test at screening and at baseline (end of RI period) ; Agreement to undertake pregnancy tests during the study and up to 30 days after randomized study treatment discontinuation; Agreement to use methods of birth control from Screening up to at least 30 days after randomized study treatment discontinuation.
- Run-in entry criteria: switched to the standardized; background antihypertensive therapy at least 4 weeks before the first RI visit; Mean trough SiSBP ≥ 140 mmHg measured by AOBPM.
- Randomization criteria: Stable dose of the standardized background antihypertensive therapy since the start of the RI period; Mean trough SiSBP ≥ 140 mmHg measured by AOBPM. |
- visita de selección Consentimiento informado firmado y fechado previo a cualquier procedimiento, Sujetos adultos de ambos sexos de al menos 18 años de edad (o edad adulta según cada país); Registros médicos de tensión arterial no controlada a pesar del tratamiento con 3 antihipertensivos en el año previo a la visita de selección Tratamiento con 3 clases farmacológicas distintas (incluido un diurético) durante al menos 4 semanas antes de la visita de selección (visita 1 Media de la PA sistólica en reposo (PASer) ≥ 140 mmHg, registrada por medición de la presión arterial en consulta automatizada (MPAC automatizada) sin supervisión, Mujeres con potencial de quedarse embarazadas solo en caso de que se cumpla lo siguiente: Prueba de embarazo negativa en la visita de selección y basal (final del periodo run in) Estar de acuerdo con ealizarse pruebas de embarazo durante el estudio y tras 30 días tras finalización del tratamiento Estar de acuerdo con el uso de métodos anticonceptivos desde la selección hasta 30 días tras la finalización del tratamiento
- criterios de inclusión en la fase "run-in" Cambio al tratamiento estandardizado Tratamiento antihipertensivo de base con una duración de al menos 4 semanas antes de la visita de "run-in" Valor medio mínimo de PASer es ≥ 140 mmHg, según MPAC automatizada.
-criterios de aleatorización: Dosis estable del tratamiento antihipertensivo estandardizado desde el inicio del periodo "run-in" Valor medio mínimo de PASer es ≥ 140 mmHg, según MPAC automatizada. |
|
E.4 | Principal exclusion criteria |
- Apparent/pseudo RHT due to white coat effect, medical inertia, poor therapeutic adherence, or secondary causes of hypertension (except sleep apnea); - Confirmed severe hypertension (grade 3) defined as SiSBP ≥ 180 mmHg and/or SiDBP ≥ 110 mmHg as measured by AOBPM at two different time points.; - Pregnant or lactating subjects; - Clinically significant unstable cardiac disease in the opinion of the investigator; - Severe renal insufficiency; - N-terminal pro-brain natriuretic peptide (NT-proBNP) > or = 200 pg/mL; - Any known factor, disease or clinically relevant medical or surgical conditions that, in the opinion of the investigator, might put the subject at risk, interfere with treatment compliance, study conduct or interpretation of the results |
- HR aparente/no real debido al síndrome de hipertensión de bata blanca, por inercia médica, por falta de cumplimiento del tratamiento o causas de hipertensión secundarias (excepto apnea del sueño). - Hipertensión grave (de grado 3) confirmada: PASer media ≥ 180 mmHg y/o presión arterial diastólica en reposo (PADer) ≥ 110 mmHg, según MPAC automatizada en dos puntos temporales distintos. - Mujeres embarazadas o lactantes - En opinión del investigador, enfermedad cardíaca inestable clínicamente significativa - Insuficiencia renal several - propéptido natriurético cerebral N-terminal (NT-proBNP) > o = a 200 pg/ml - cualquier factor conocido, enfermedad o condición médica o quirúrgica clínicamente relevante que en opinión del investigador puede poner al paciente en riesgo, interfiera en la adherencia al tratamiento, el desarrollo del estudio o la interpretación de los resultados
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|
E.5 End points |
E.5.1 | Primary end point(s) |
- Change from baseline to Week 4 of double-blind (DB) treatment in mean trough SiSBP measured by AOBPM. |
- El criterio de valoración principal de la eficacia es el cambio en el valor medio mínimo de la PASer, según MPAC automatizada, desde el momento basal hasta la semana 4 del tratamiento a DC |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline to Week 4 after treatment initiation. |
desde el momento basal hasta la semana 4 del tratamiento |
|
E.5.2 | Secondary end point(s) |
- Change from Week 36 (i.e., start of double-blind withdrawal [DB-WD]) to Week 40 in mean trough SiSBP measured by AOBPM - Change from baseline to Week 4 of DB treatment in trough Sitting Diastolic BP (SiDBP) measured by AOBPM; - Changes from baseline to Week 4 of DB treatment in 24-h mean SBP and DBP measured by ABPM; - Change from Week 36 to Week 40 of DB-WD treatment in mean trough SiDBP measured by AOBPM; - Changes from Week 36 to Week 40 of DB-WD treatment in 24-h mean SBP and DBP measured by ABPM. |
- Cambio en el valor medio mínimo de PADer desde la semana 36 hasta la semana 40 del tratamiento de RF DC, registrado mediante MPAC automatizada. - Cambio en el valor medio mínimo de la PADer, desde el momento basal hasta la semana 4 del tratamiento a DC, registrado mediante MPAC automatizada. - Cambios en los valores promedio de 24 h de presión arterial sistólica (PAS) y presión arterial diastólica (PAD), desde el momento basal hasta la semana 4 del tratamiento a DC, registrados mediante monitorización ambulatoria de la presión arterial (MAPA). - Cambios en la PADer medida por MPAC automatizada desde la semana 36 hasta la semana 40 - Cambios en los valores promedio de 24 h de PAS y PAD del tratamiento de RF DC, desde la semana 36 hasta la semana 40, registrados mediante MAPA. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline to week 4, or from week 36 to week 40. |
Desde basal hasta la semana 4, o desde la semana 36 a la semana 40 |
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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 | No |
E.8.1.3 | Single blind | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Ciego simple con placebo, preinclusión/aleatorización con tres partes: DB, SB y DB-WS |
SB placebo run-in/randomized with 3 parts: (DB), (SB) and (DB-WD) |
|
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 | 6 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 | Yes |
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 |
Australia |
Belgium |
Canada |
China |
Czech Republic |
Finland |
France |
Germany |
Hungary |
Italy |
Korea, Republic of |
Netherlands |
Poland |
Russian Federation |
Spain |
Switzerland |
United Kingdom |
United States |
|
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
|
End of the trial is defined as last subject last visit (LSLV) |
El fin del ensayo será la última visita del último paciente |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 33 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 33 |