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 |
In PAH, the pulmonary arteries, carrying blood from the heart to the lungs where it picks up oxygen, constrict abnormally, forcing the heart to work faster and blood pressure within the lungs to rise. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
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 assess the hemodynamic effects of APD811 and the effect of APD811 on 6MWD in patients with PAH after 22 weeks of treatment including an initial dose titration period of up to 9 weeks |
El objetivo principal del ensayo clínico es evaluar los efectos hemodinámicos del APD811 y el efecto del APD811 sobre la prueba de distancia de marcha de seis minutos (DM6M) en pacientes con hipertensión arterial pulmonar (HAP) después de 22 semanas de tratamiento, que incluye un período inicial de titulación de dosis de hasta 9 semanas. |
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E.2.2 | Secondary objectives of the trial |
The secondary objecives of the study are:
-To assess the safety and tolerability of APD811
-To assess the effect of APD811 in clinical worsening
Exploratory objectes of the study are:
-To assess the effect of APD811 on levels of BNP and NT-proBNP after22 weeks of treatment
-To assess change in WHO/NYHA functional class
-To evaluate the pharmacokinetics (Cmin and presumptive Cmax) of oral APD811
-To evaluate the effects of APD811 on systemic vascular resistance (SVR) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Males or females aged 18-75 years, inclusive
-Symptomatic WHO Group 1 PAH classified by one of the following subgroups:
*Idiopathic PAH (IPAH)
*Heritable PAH (HPAH)
*Drugs and toxins induced
*Associated with PAH (APAH); specifically connective tissue diseases, HIV infection and congenital heart disease
-Has had the diagnosis of PAH confirmed by cardiac catheterization
-Has WHO/NYHA functional class II-IV symptomatology
-Previously diagnosed with PAH on stable oral disease-specific PAH therapy with either an ERA and/or an agent acting on the nitric oxide pathway, i.e. a PDE-5 inhibitor or a soluble guanlyate cyclase stimulator. Stable is defined as no change in dose within 3 months of the start of Screening and for the duration of the study
-Has 6MWT distances of 100-500 m, and within 15% of each other on 2 consecutive tests done on differnt days at Screening
-Has pulmonary function tests (PFTs) within 6 months prior to the start of Screening with no evidence of significant parenchymal lung disease
-Has a ventilation-perfusion (V/Q) lung scan or pulmonary angiogram within 5 years prior to Screening and concomitant with or following diagnosis of PAH that shows no evidence of thromboembolic disease
-If on vasodilators (including calcium channel blockers), digoxin, spironolactone, or L-Arginine supplementation; the patient must be on a stable dose for at least 1 month prior to the start of Screening |
• Hombres o mujeres de entre 18 y 75 años de edad, inclusive.
• HAP sintomática de grupo 1 según la OMS, clasificada en uno de los siguientes subgrupos:
• Hipertensión arterial pulmonar idiopática (HAPI).
• Hipertensión arterial pulmonar familiar (HAPF).
• Fármacos y toxinas inducidas.
• Hipertensión arterial pulmonar asociada (HAPA), específicamente con enfermedades del tejido conectivo, infección de VIH y cardiopatía congénita.
• Se ha confirmado el diagnóstico de HAP por un cateterismo cardíaco.
• Tiene una sintomatología de la clase funcional II a IV de la OMS y la NYHA.
• Previamente se le ha diagnosticado HAP y recibe una terapia oral específica contra la HAP estable con un ARE y/o un agente que actúa sobre la vía del óxido nítrico, es decir, un inhibidor de la PDE5 o un estimulador soluble de la guanilato ciclasa. "Estable" se define como una dosis sin modificaciones dentro de los 3 meses después del comienzo de la selección y durante todo el ensayo clínico.
• Presenta distancias de 100 a 500 m en la PM6M y se encuentran dentro del 15 % una de la otra en 2 pruebas consecutivas realizadas en diferentes días durante la selección.
Tiene pruebas de función pulmonar (PFP) dentro de los 6 anteriores al comienzo de la selección, sin evidencia de enfermedad del parénquima pulmonar significativa.
• Tiene un escáner pulmonar de ventilación/perfusión (V/Q) o un angiograma pulmonar dentro de los 5 años anteriores a la selección, en relación con o después del diagnóstico de HAP, que no muestra evidencia de enfermedad tromboembólica.
• Si se administran vasodilatadores (que incluyen calcioantagonistas), digoxina, espironolactona o suplementos de L-arginina, el paciente debe mantener una dosis estable durante al menos 1 mes antes del comienzo de la selección. |
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E.4 | Principal exclusion criteria |
-Newly diagnosed with PAH and on no disease-specific PAH therapy
-Previous participation in any clinical study with an investigational drug, biologic, or device within 2 months prior to the Screening visit
-Acutely decompensated heart failure within 1 month prior to start of Screening
-Systolic blood pressure <90 mm Hg at Screening
-Evidence or history of left-sided heart disease and/or clinically significant cardiac disease
-Use or chronic administration (defined as >30 days) of a prostacyclin or prostacyclin analogue within 3 months of Screening
-Any previous use of a prostacyclin or prostacyclin analogue that was stopped for safety or tolerability issues associated with pharmacology/mechanism of action
-Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into the study |
• Diagnosticado recientemente con HAP y que no recibe una terapia específica contra la HAP.
• Participación previa en un ensayo clínico con un fármaco, un producto biológico o un dispositivo en investigación dentro de los 2 meses anteriores a la visita de selección.
• Insuficiencia cardíaca con descompensación aguda 1 mes antes de la selección.
• Presión sanguínea sistólica <90 mm Hg durante la selección.
• Evidencia o antecedentes de cardiopatía izquierda y/o cardiopatía significativa a nivel clínico.
• Uso o administración crónica (que se define como más de 30 días) de prostaciclina o un análogo de la prostaciclina dentro de los 3 meses posteriores a la selección.
• Cualquier uso previo de prostaciclina o un análogo de la prostaciclina que se suspendió por motivos de seguridad o tolerancia relacionados con la farmacología o el mecanismo de acción.
• Otras anormalidades de laboratorio o anormalidades médicas crónicas o agudas graves que puedan aumentar el riesgo relacionado con la participación en el ensayo clínico o la administración del producto en investigación o que puedan interferir con la interpretación de los resultados del ensayo clínico y, a criterio del investigador, descalificarían al paciente para participar en este ensayo clínico. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy Endpoints:
Efficacy will be assessed by measurement of pulmonary vascular resistance (PVR) obtained on RHC, measurement of B-type natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and six-minute walk test (6MWT).
*Change from baseline in PVR
*Change from baseline in 6MWD |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Measurement of pulmonary vascular resistance (PVR) obtained on right heart catheterization (RHC)
At Screening and at End Of Study Visit
6MWT
Two 6MWTs are required during Screening and each test must be performed on a separate day
At day 35 of the Dose Titration Period
On Day 70/Week 10, Day 98/Week 14, Day 126/Week 18 of the Treatment Period and at the End Of Study Visit (EOS) (Day 154/Week 22)
Plus at the Follow-up Visit (Start of OLE) (Day 175/Week 25) |
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E.5.2 | Secondary end point(s) |
Secondary:
*Percent change from baseline in PVR
*Proportion of subjects who exhibit clinical worsening
Exploratory:
*Change from baseline in BNP/NT-proBNP
*Change from baseline in WHO/NYHA functional class
*Change from baseline in other hemodynamic parameters (e.g. SVR) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Measurement of B-type natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptie (NT-proBNP) levels
At day 1 of Dose Titration Period
Study Day 70/Study Week 10 of the Treatment Perid and at End Of Study Visit (Day 154/Week 22)
Plus at the Follow-up Visit (start of OLE) (Day 175/Week 25)
Assessment of clinical worsening at each study visit |
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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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
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 | 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 | 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 | 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 | 3 |
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 |
Australia |
Bulgaria |
Czech Republic |
Hungary |
Poland |
Romania |
Serbia |
Spain |
United States |
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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 | 8 |
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 | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |