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 |
Hipertensión arterial pulmonar |
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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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the PK profile of different zamicastat doses in PAH patients to find the most promising therapeutic dosage range for the treatment of PAH disease |
Evaluar el perfil de farmacocinética (PK) de diferentes dosis de zamicastat en pacientes con HAP para encontrar el rango de dosis terapéuticas más prometedor para el tratamiento de la HAP |
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E.2.2 | Secondary objectives of the trial |
To assess further PK parameters, efficacy, safety and tolerability of different zamicastat doses |
Evaluar otros parámetros PK, eficacia, seguridad y tolerabilidad de diferentes dosis de zamicastat |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients aged 18 to 65 years. 2. Able to comprehend and willing to sign an informed consent form. 3. Diagnosis of PAH (pulmonary arterial hypertension WHO Group 1), documented by right heart catheterisation with a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and a pulmonary vascular resistance (PVR) > 3 WU [Galie N, et. al 2015; Lau EMT, et. al. 2017]: a) Idiopathic, in non-vasoreactive patients b) Heritable: Bone morphogenetic protein receptor type II (BMPR2) mutation and other mutations, in non-vasoreactive patients c) Drugs and toxin induced, in non-vasoreactive patients d) Associated with connective tissue disease or with simple congenital defects (atrial septal defect and/or ventricular septal defect) if closed > 12 months before inclusion. 4. WHO functional class II or III as judged by the investigator. 5. Stable treatment with at least one of the following approved oral PAH therapies within 3 months before V1: Ambrisentan, Bosentan, Macitentan, Riociguat, Selexipag, Sildenafil or Tadalafil. |
1. Pacientes hombre o mujer de 18 a 65 años. 2. Capaces de comprender y dispuestos a firmar un formulario de consentimiento informado. 3. Diagnóstico de HAP (hipertensión arterial pulmonar, grupo 1 de la OMS), documentado mediante cateterismo del corazón derecho con una presión arterial pulmonar media (PAPM) ≥ 25 mmHg, una presión arterial pulmonar en cuña (PAPC) ≤ 15 mmHg y una resistencia vascular pulmonar (RVP) > 3 WU [Galie N, et. al 2015; Lau EMT, et. al. 2017]: a) Idiopática, en pacientes no vasorreactivos b) Hereditaria: Mutación del receptor de proteína morfogenética ósea tipo II (BMPR2) y otras mutaciones, en pacientes no vasorreactivos c) Inducida por fármacos y toxinas, en pacientes no vasorreactivos d) Asociada con enfermedad del tejido conectivo o con defectos congénitos simples (defecto del tabique auricular y/o defecto del tabique ventricular) si se cierra > 12 meses antes de la inclusión. 4. Clase funcional II o III de la OMS, a juicio del investigador. 5. Tratamiento estable con al menos una de las siguientes terapias orales de HAP aprobadas dentro de los 3 meses anteriores a la V1: Ambrisentan, Bosentan, Macitentan, Riociguat, Selexipag, Sildenafil o Tadalafil. |
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E.4 | Principal exclusion criteria |
1. Contraindication to zamicastat, i.e. known hypersensitivity to ingredients of zamicastat formulation. 2. Persistent hypotension defined as SBP < 95 mmHg or DBP < 50 mmHg. 3. Uncontrolled diabetes mellitus. 4. PAH WHO Group 1 due to portal hypertension, human immunodeficiency virus (HIV) infection and schistosomiasis. 5. Any disease known to cause pulmonary hypertension other than PAH WHO Group 1, e.g. obstructive lung diseases, parasitic disease affecting the pulmonary system, sickle cell anaemia, left heart disease. 6. History of moderate to severe hepatic impairment (Child-Pugh B and C). 7. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (measured at V1). 8. Use of the following prohibited medication or treatments during study participation: calcium channel blockers (CCBs) if used for the treatment of PAH in vasoreactive patients; drugs containing a catechol group that is metabolised by DβH e.g. rimiterole, isoprenaline, dopamine, dopexamine or dobutamide) or α- and/or β-blockers. 9. Current or previous (within the past year) alcohol or substance abuse excluding caffeine or nicotine. 10. Presence of any other significant or progressive/unstable medical condition that, in the opinion of the investigator, would compromise evaluation of the study treatment or may jeopardise the patient’s safety, compliance or adherence to protocol requirements. 11. For women: Pregnancy or breast-feeding. Women of childbearing potential unable or unwilling to undergo pregnancy tests and practice acceptable contraceptive measures. Acceptable methods for women are surgical intervention (e.g. bilateral tubal occlusion),intrauterine device, double-barrier methods and true sexual abstinence (i.e. when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. 12. Previous participation in any other drug investigational study within the past 30 days (or five half-lives of investigational medicinal product [IMP] whichever is longer) prior to V1. 13. Vulnerable patients according to Section 1.61 of the ICH guideline for Good Clinical Practice E6. |
1. Contraindicación para zamicastat, es decir, hipersensibilidad conocida a los ingredientes de la formulación de zamicastat. 2. Hipotensión persistente definida como PAS < 95 mmHg o PAD < 50 mmHg. 3. Diabetes mellitus no controlada. 4. HAP grupo 1 de la OMS debido a hipertensión portal, infección por el virus de la inmunodeficiencia humana (VIH) y esquistosomiasis. 5. Cualquier enfermedad que se sepa que causa hipertensión pulmonar diferente a HAP grupo 1 de la OMS, como por ejemplo enfermedades pulmonares obstructivas, enfermedad parasitaria que afecte el sistema pulmonar, anemia de células falciformes, síndrome del corazón izquierdo. 6. Historial de insuficiencia hepática moderada a grave (Child-Pugh B y C). 7. Velocidad de filtración glomerular estimada (VFGe) < 30 ml/min/1,73 m2 (medida en la V1). 8. Uso de las siguientes medicaciones o tratamientos prohibidos durante la participación en el estudio: bloqueadores de los canales de calcio (BCC) si se usan para el tratamiento de la HAP en pacientes vasorreactivos; fármacos que contienen un grupo catecol que se metaboliza por DβH, como por ejemplo rimiterol, isoprenalina, dopamina, dopexamina o dobutamina) o α- y/o β-bloqueantes. 9. Abuso de alcohol o sustancias en la actualidad o en el pasado (en el último año), excluida la cafeína o la nicotina. 10. Presencia de cualquier afección médica inestable/progresiva o significativa que, en opinión del examinador, pueda comprometer la evaluación del tratamiento del estudio o pueda poner en peligro la seguridad del paciente, el cumplimiento o el seguimiento de los requisitos del protocolo. 11. Para mujeres: Embarazo o lactancia. Las mujeres en edad fértil que no pueden o no desean someterse a pruebas de embarazo y a la práctica de medidas anticonceptivas admisibles. Los métodos admisibles para las mujeres son la intervención quirúrgica (p. ej., ligadura de trompas bilateral), el dispositivo intrauterino, los métodos de barrera doble y la abstinencia sexual efectiva (es decir, cuando esta se ajusta al estilo de vida normal y de preferencia del paciente). La abstinencia periódica (p. ej., método del calendario, de la temperatura, de la posovulación) y el método de marcha atrás no son métodos anticonceptivos admisibles. 12. Participación previa en cualquier estudio de un fármaco en investigación en los últimos 30 días (o cinco semividas del producto en fase de investigación [PEI], lo que sea mayor) antes de la V1. 13. Pacientes vulnerables de acuerdo con la Sección 1.61 de la directriz ICH de Buenas Prácticas Clínicas E6. |
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E.5 End points |
E.5.1 | Primary end point(s) |
To evaluate pharmacokinetic (PK) profile of different zamicastat doses in PAH patients to find the most promising therapeutic dosage range for the treatment of PAH disease |
Evaluar el perfil de farmacocinética (PK) de diferentes dosis de zamicastat en pacientes con HAP para encontrar el rango de dosis terapéuticas más prometedor para el tratamiento de la HAP |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Once the last PK sample of the last patient has been analysed. |
Una vez analizada la última muestra PK del último paciente. |
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E.5.2 | Secondary end point(s) |
To assess further PK parameters, efficacy, safety and tolerability of different zamicastat doses |
Evaluar otros parámetros PK, eficacia, seguridad y tolerabilidad de diferentes dosis de zamicastat |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Once the last PK, efficacy, safety and tolerability parameters of the last patient has been analysed. |
Una vez analizados los últimos parámetros de PK, seguridad y tolerabilidad del último paciente. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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 | 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 | No |
E.8.2.3 | Other | No |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
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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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LVLS |
Última visita del último sujeto |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |