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    EudraCT Number:2013-003462-14
    Sponsor's Protocol Code Number:AC-055-310
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-12-05
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2013-003462-14
    A.3Full title of the trial
    A multi-center, open-label, single-arm, Phase 3b study of macitentan in patients with pulmonary arterial hypertension to psychometrically validate the French, Italian and Spanish versions of the PAH-SYMPACT?

    Estudio fase IIIb con Macitentan, multicéntrico, abierto, de una única rama, en pacientes con hipertensión arterial pulmonar para validar psicométricamente las versiones francesa, italiana y española de PAH-SYMPACT™
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of the drug macitentan in patients with pulmonary arterial hypertension in order to test the French, Italian, and Spanish translations of a patient questionnaire called PAH-SYMPACT.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberAC-055-310
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorACTELION Pharmaceuticals Ltd.
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportACTELION Pharmaceuticals Ltd.
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationActelion Pharmaceuticals Ltd.
    B.5.2Functional name of contact pointGlobal Medical Information
    B.5.3 Address:
    B.5.3.1Street AddressGewerbestrasse 16
    B.5.3.2Town/ cityAllschwil
    B.5.3.3Post code4123
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/11/909
    D.3 Description of the IMP
    D.3.1Product namemacitentan
    D.3.2Product code ACT-064992
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMACITENTAN
    D.3.9.1CAS number 441798-33-0
    D.3.9.2Current sponsor codeACT-064992
    D.3.9.4EV Substance CodeSUB89247
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pulmonary arterial hypertension

    Hipertensión arterial pulmonar
    Hipertensión arterial pulmonar
    E.1.1.1Medical 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.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10064911
    E.1.2Term Pulmonary arterial hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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™.
    E.2.2Secondary 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).
    E.2.3Trial contains a sub-study No
    E.3Principal 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•cm5 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.
    E.4Principal 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.
    E.5 End points
    E.5.1Primary 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
    E.5.1.1Timepoint(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
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Visits 1, 2, 3, 4 and 5
    visitas 1,2,3,4 y 5
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Psychometric characteristics of reliability and construct validity of the French, Italian and Spanish versions of the PAH-SYMPACT?
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other 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.8.4.1Number of sites anticipated in Member State concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state53
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 160
    F.4.2.2In the whole clinical trial 160
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    An extension study will be considered for patients who complete the 16 weeks of treatment as scheduled.
    La extensión del estudio puede considerarse para pacientes que completen las 16 semanas de tratamiento.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-02-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-09-09
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