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    Summary
    EudraCT Number:2014-004624-21
    Sponsor's Protocol Code Number:AC-055-404
    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:2015-03-03
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2014-004624-21
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled, prospective, multicenter, parallel group study to assess the safety and efficacy of macitentan in patients with portopulmonary hypertension
    Estudio aleatorizado, con doble enmascaramiento, controlado con placebo,
    prospectivo, multicéntrico y con grupos paralelos para evaluar la seguridad
    y eficacia de macitentán en pacientes con hipertensión portopulmonar
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of a new therapeutic agent used to treat portopulmonary hypertension
    Estudio de un nuevo agente terapéutico para tratar la hipertensión portopulmonar
    A.3.2Name or abbreviated title of the trial where available
    PORTICO
    A.4.1Sponsor's protocol code numberAC-055-404
    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.1.3.4CountrySwitzerland
    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.4.2CountrySwitzerland
    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
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+34900811 335
    B.5.6E-mailmedinfo@actelion.com
    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 Yes
    D.2.1.1.1Trade name Opsumit
    D.2.1.1.2Name of the Marketing Authorisation holderActelion Registration Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Portopulmonary hypertension
    Hipertensión portopulmonar
    E.1.1.1Medical condition in easily understood language
    Portopulmonary Hypertension is a condition in which the pressure in the blood vessels going to the lungs (the pulmonary arteries) is higher than normal due to an underlying liver disease
    La hipertensión portopulmonar es una afección donde la presión en los vasos sanguíneos que van a los pulmones (arterias pulmonares) es más alta de lo normal por a una enfermedad hepática subyacente
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10067281
    E.1.2Term Portopulmonary 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 effect of macitentan on pulmonary vascular resistance (PVR) as compared to placebo in patients with portopulmonary hypertension
    Evaluar el efecto de macitentán, comparado con un placebo, sobre la resistencia vascular pulmonar (RVP) en pacientes con hipertensión portopulmonar (HPoP).
    E.2.2Secondary objectives of the trial
    - To evaluate the effect of macitentan as compared to placebo on cardio-pulmonary hemodynamics, hepatic portal vein pressure, disease severity, and exercise capacity in patients with PoPH.
    - To evaluate the safety and tolerability of macitentan as compared to placebo in patients with PoPH
    - To evaluate the pharmacokinetics (PK) of macitentan and its active metabolite ACT-132577 in subjects with PoPH
    - Evaluar el efecto de macitentán, comparado con un placebo,
    sobre las características hemodinámicas cardiopulmonares, la tensión en la vena porta hepática, la intensidad de la enfermedad y la capacidad de realizar ejercicio en pacientes con HPoP.
    - Evaluar la seguridad y la tolerabilidad de macitentán comparado con un placebo en pacientes con HPoP.
    - Evaluar las características farmacocinéticas (FC) del macitentán y de su metabolito activo, el ACT-132577, en pacientes con HPoP.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    PK sub-study

    At least 20 patients eligible for the open-label treatment period will be enrolled. The plasma PK parameters will be derived by non-compartmental analysis of the plasma concentration-time profiles.
    PK endpoints are for both macitentan and ACT-132577:
    - The area under the plasma concentration-time curve during one dosing interval (AUCt).
    - Maximum plasma concentration (Cmax) during a dosing interval.
    - The time to reach maximum plasma concentration (tmax) during a dosing interval.
    Subestudio FC

    Se inscribirán al menos 20 pacientes aptos para el periodo de tratamiento sin enmascaramiento. Las variables FC plasmáticas se inferirán del análisis no compartimental de los valores de concentración plasmática frente al tiempo. Los valores correspondientes a la concentración máxima en plasma (Cmáx) y al área bajo la curva de concentración plasmática frente al tiempo durante el intervalo de dosis (ABCt) se supone que siguen una distribución normal logarítmica. Los criterios de valoración FC son los mismos para macitentán y para ACT-132577:
    - Área bajo la curva de concentración plasmática frente al tiempo durante un intervalo de dosis (ABCt).
    - Concentración máxima en plasma (Cmáx) durante un intervalo de dosis.
    - Periodo de tiempo hasta alcanzar la concentración máxima en plasma (tmáx) durante un intervalo de dosis.
    E.3Principal inclusion criteria
    1) Male or female >/= 18 years of age with symptomatic PoPH:
    Documented diagnosis of portal hypertension
    PAH by right-heart catheterization at screening
    - Mean pulmonary arterial pressure (mPAP) >/= 25 mmHg
    - Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) </= 15 mmHg
    2) Pulmonary vascular resistance (PVR) >/= 4 Wood Units or >/= 320 dyn.s.cm-5 at screening
    3) 6MWD >/= 50 m at screening
    1) Hombre o mujer >/= 18 años con HPoP sintomática:
    Diagnóstico confirmado de hipertensión portal
    HAP detectada mediante cateterismo en el hemicardio derecho en la selección:
    - Presión arterial pulmonar media (PAPm) >/= 25 mm Hg
    - Presión de enclavamiento arterial pulmonar (PEAP) o tensión telediastólica ventricular izquierda (TTDVI) </= 15 mm Hg
    2) RVP >/= 4 unidades Wood (UW) o >/= 320 dyn.s.cm-5 en la
    selección
    3) Distancia recorrida durante 6 minutos a pie (6MWD) >/= 50 m en la selección
    E.4Principal exclusion criteria
    1. Severe hepatic impairment, as defined by Child-Pugh Class C liver disease or MELD score >/= 19
    2. Systolic blood pressure (SBP) < 90 mmHg at Screening
    3. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >/= 3 X the upper limit of the normal range (ULN) at Screening
    4. Bilirubin >/= 3 mg/dL at Screening
    5. Grades 2, 3, or 4 hepatic encephalopathy
    6. History of liver transplantation or transplantation expected within 3 months after randomization
    7. Gastrointestinal bleeding or esophageal varices bleeding < 3 months prior to randomization
    8. Treatment with endothelin receptor antagonists (ERA), i.v./s.c. or oral prostanoids within 3 months prior to randomization
    9. Treatment with interferon within 3 months prior to randomization
    10. Treatment with strong cytochrome P450 (CYP) 3A4 inducers within 4 weeks prior to randomization
    11. Treatment with strong CYP3A4 inhibitors within 4 weeks prior to randomization
    1. Insuficiencia hepática grave, según se define en la clase C de la clasificación Child-Pugh de hepatopatías, o un valor ? 19 para el modelo de hepatopatía en fase terminal (MHPFT)
    2. Tensión arterial sistólica (TAS) < 90 mm Hg en la selección
    3. Aspartato aminotransferasa (AST) sérica y/o alanina aminotransferasa (ALT) sérica >/= 3 x el límite superior de la normalidad (LSN) en la selección
    4. Bilirrubina >/= 3 mg/dl en la selección
    5. Encefalopatía hepática de grado 2, 3 o 4
    6. Antecedentes de trasplante de hígado u operación de trasplante prevista en los 3 meses posteriores a la aleatorización
    7. Hemorragia gastrointestinal o varices esofágicas sangrantes
    < 3 meses antes de la aleatorización
    8. Recibir tratamiento con antagonistas del receptor endotelínico (ARE), por vía intravenosa/subcutánea (i.v./s.c.) o prostanoides orales en los 3 meses antes de la aleatorización
    9. Tratamiento con interferón en los 3 meses anteriores a la aleatorización
    10. Tratamiento con inductores potentes del citocromo P450
    (CYP) 3A4 en las 4 semanas anteriores a la aleatorización
    11. Tratamiento con inhibidores potentes del CYP3A4 en las 4 semanas anteriores a la aleatorización
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy endpoint
    Relative change from Baseline to Week 12 in PVR.
    Criterio principal de valoración de la eficacia
    Cambio relativo en la RVP desde el valor de partida hasta la semana 12.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Screening, Week 12
    Selección, semana 12
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints
    - Change from Baseline to Week 12 in mean right atrial pressure (mRAP), mean pulmonary arterial pressure (mPAP), cardiac index (CI), total pulmonary resistance (TPR), and mixed venous oxygen saturation (SVO2), all measured at rest
    - Change from Baseline to Week 12 in 6-minute walk distance (6MWD)
    - Change from Baseline to Week 12 in WHO functional class
    - Change from Baseline to Week 12 in NT-proBNP

    Other efficacy endpoints
    - Change from Baseline to Week 12 in hepatic venous pressure gradient (HVPG)
    - Change from Baseline to Week 12 in Borg dyspnea index
    Criterios secundarios de valoración de la eficacia
    - Cambio desde el valor de partida hasta la semana 12 en la presión auricular derecha media (PADm), presión arterial pulmonar media (PAPM), índice cardíaco (IC), resistencia total pulmonar (RTP) y en saturación venosa mixta de oxígeno (SVO2), todas las medidas realizadas en reposo.
    - Cambio en la 6MWD desde el valor de partida hasta la semana 12.
    - Cambio en la clase funcional de la OMS desde el valor de partida hasta la semana 12.
    - Cambio en la NT-proBNP desde el valor de partida hasta la semana 12.

    Otros criterios de valoración de la eficacia
    - Cambio en el gradiente de presión venosa hepática (GPVH) desde el valor de partida hasta la semana 12.
    - Cambio en el valor de la escala Borg de la disnea desde el valor de partida hasta la semana 12.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Mean right atrial pressure (mRAP), mean pulmonary arterial pressure (mPAP), cardiac index (CI), total pulmonary resistance (TPR), and mixed venous oxygen saturation (SVO2), all measured at rest: Screening, Day 1, Week 12

    - 6-minute walk distance (6MWD): Screening, Day 1, Week 4/8, Week 12

    - WHO functional class: Screening, Day 1, Week 4/8, Week 12

    - NT-proBNP: Screening, Day 1, Week 12

    -Hepatic venous pressure gradient (HVPG): Screening, Week 12

    - Borg dyspnea index: Screening, Day 1, Week 4/8, Week 12
    - Cambio desde el valor de partida hasta la semana 12 en la presión auricular derecha media (PADm), presión arterial pulmonar media (PAPM), índice cardíaco (IC), resistencia total pulmonar (RTP) y en saturación venosa mixta de oxígeno (SVO2), todas las medidas realizadas en reposo: selección, día 1, semana 12

    - Distancia recorrida durante 6 minutos a pie (6MWD): selección, día 1, semana 4/8, semana 12

    - Clase funcional de la OMS: selección, día 1, semana 4/8, semana 12

    - NT-proBNP: selección, día 1, semana 12

    - Gradiente de presión venosa hepática (GPVH): selección, semana 12

    - Valor de la escala Borg de la disnea: selección, día 1, semana 4/8, semana 12
    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 Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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 No
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Brazil
    Czech Republic
    France
    Germany
    Spain
    United Kingdom
    United States
    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
    LVLS (Last 30-day Safety follow up)
    Última visita del último paciente (pasados 30 días del seguimiento de seguridad)
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    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: 74
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 32
    F.4.2.2In the whole clinical trial 84
    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)
    The investigator/delegate will explain to subjects what treatment(s)/medical care is necessary and available according to local regulations.
    El investigador o su delegado explicará a los pacientes qué tratamiento(s) / atención médica son necesarios y están disponibles de acuerdo con la legislación local.
    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 Decision2015-04-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-10-31
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