Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42869   clinical trials with a EudraCT protocol, of which   7063   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2014-004786-25
    Sponsor's Protocol Code Number:AC-077A301
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-06-11
    Trial 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 number2014-004786-25
    A.3Full title of the trial
    Prospective, multi-center, double-blind, randomized, active-controlled, triple-dummy, parallel-group, group-sequential, adaptive Phase 3 clinical study to compare the efficacy and safety of macitentan and tadalafil monotherapies with the corresponding fixed dose combination in subjects with pulmonary arterial hypertension (PAH), followed by an open-label treatment period with macitentan and tadalafil fixed dose combination therapy
    Estudio clínico de fase 3 prospectivo, multicéntrico, doble ciego, aleatorizado, controlado con producto activo, triple simulado, de grupo paralelo, secuencial y adaptativo para comparar la eficacia y seguridad de las monoterapias de macitentán y tadalafilo con la combinación de dosis fija correspondiente en pacientes con hipertensión arterial pulmonar (HAP), seguidas de un periodo de tratamiento abierto con una combinación de dosis fija de macitentán y tadalafilo
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to compare the efficacy and safety of macitentan and tadalafil monotherapies with the corresponding fixed dose combination in subjects with pulmonary arterial hypertension (PAH).
    Estudio clínico para comparar la eficacia y seguridad de las monoterapias de macitentán y tadalafilo con la combinación de dosis fija correspondiente en pacientes con hipertensión arterial pulmonar (HAP)
    A.4.1Sponsor's protocol code numberAC-077A301
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03904693
    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 pointClinical Trial Disclosure Desk
    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.5.6E-mailclinical-trials-disclosure@its.jnj.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code ACT-064992D
    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.3.9.4EV 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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTADALAFIL
    D.3.9.1CAS number 171596-29-5
    D.3.9.4EV Substance CodeSUB12602MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Adcirca®
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V.
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    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 INNTADALAFIL
    D.3.9.1CAS number 171596-29-5
    D.3.9.4EV Substance CodeSUB12602MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 holderJanssen-Cilag International NV
    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.3.9.4EV 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
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    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
    Pulmonary Arterial Hypertension
    Hipertensión arterial pulmonar
    E.1.1.1Medical condition in easily understood language
    Pulmonary Arterial Hypertension is an increase in blood pressure in the pulmonary arteries leading to shortness of breath, dizziness, fainting and other symptoms.
    La hipertensión arterial pulmonar es un aumento de la presión arterial en las arterias pulmonares que provoca dificultad para respirar, mareos, desmayos y otros síntomas.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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
    1. To evaluate the effect of the macitentan/tadalafil fixed dose combination (M/T FDC) vs macitentan 10 mg alone on PVR at EDBT in subjects with symptomatic WHO Group 1 PAH who are PAH-specific treatment-naïve or are currently being treated with an ERA as monotherapy.
    2. To evaluate the effect of the M/T FDC vs tadalafil 40 mg alone on PVR at EDBT in subjects with symptomatic WHO Group 1 PAH who are PAH-specific treatment-naïve or are currently being treated with a PDE-5i as monotherapy.
    1. Evaluar el efecto de la combinación de dosis fija (CDF) de macitentán 10 mg y tadalafilo 40 mg frente a macitentán 10 mg en monoterapia sobre la resistencia vascular pulmonar (RVP) al fin del tratamiento doble ciego (FTDC) en pacientes con HAP sintomática del grupo 1 de la OMS que no han recibido tratamiento específico para la HAP o que están siendo tratados actualmente con un antagonista de los receptores de endotelina (ARE) como monoterapia
    2. Evaluar el efecto de la CDF de macitentán 10 mg y tadalafilo 40 mg frente a tadalafilo 40 mg en monoterapia sobre la RVP al llegar al FTDC en pacientes con HAP sintomática del grupo 1 de la OMS que no han recibido tratamiento específico para la HAP o que están siendo tratados actualmente con un inhibidor de la fosfodiesterasa tipo 5 (iFDE-5) como monoterapia.
    E.2.2Secondary objectives of the trial
    • To evaluate the effect of the M/T FDC compared to the respective monotherapies on:
    - Exercise capacity
    - PAH symptoms and their impacts on subject’s life.
    - WHO FC.
    • To evaluate the safety and tolerability of the M/T FDC in the subject population.
    • Evaluar el efecto de la CDF de macitentán/tadalafilo (M/T) en comparación con las monoterapias respectivas sobre:
    - Capacidad para hacer ejercicio.
    - Síntomas de la HAP y sus efectos en la vida de los pacientes.
    - Clase funcional (CF) de la OMS.
    - Evaluar la seguridad y tolerabilidad de la CDF de M/T en la población de pacientes.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed and dated ICF.
    2. Male and female subjects ≥ 18 years old and ≤ 75 years old.
    3. Confirmed diagnosis of symptomatic PAH in WHO FC II or III.
    4. Symptomatic PAH belonging to one of the following subgroups of WHO Group 1 pulmonary hypertension [Simonneau 2013]:
    − Idiopathic.
    − Heritable.
    − Drug- or toxin-induced.
    − Associated with one of the following:
    o Connective tissue disease.
    o HIV infection.
    o Portal hypertension.
    o Congenital heart disease with simple systemic-to-pulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus) with persistent pulmonary hypertension documented by an RHC ≥ 1 year after surgical repair.
    5. PAH diagnosis confirmed by hemodynamic evaluation at rest, evaluated within 5 weeks prior to randomization:
    − Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, AND
    − Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg, AND
    − Pulmonary vascular resistance (PVR) ≥ 3 WU (i.e., ≥ 240 dyn∙sec∙cm−5)
    6. Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH
    7. No history of PAH-specific treatment or currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 months prior to baseline RHC, within the following prespecified doses:
    - Bosentan: 250 mg total daily dose
    - Macitentan: 10 mg total daily dose
    - Ambrisentan: 10 mg total daily dose
    - Sildenafil: 60–120 mg total daily dose
    - Tadalafil: 40 mg total daily dose
    - Vardenafil: 10 mg total daily dose
    8. Subject able to perform the 6MWT with a minimum distance of 100 m and maximum distance of 450 m at Screening.
    9. A woman of childbearing potential is eligible only if the following applies:
    - Negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization.
    - Agreement to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation.
    - Agreement to follow the contraception scheme from Screening up to at least 30 days after study treatment discontinuation.
    1. Formulario de consentimiento informado firmado y fechado.
    2. Pacientes masculinos y femeninos ≥18 años y ≤75 años.
    3. Diagnóstico confirmado de HAP sintomática con CF II o III de la OMS.
    4. HAP sintomática perteneciente a uno de los siguientes subgrupos de hipertensión pulmonar del grupo 1 de la OMS [Simonneau 2013]:
    - Idiopática.
    - Hereditaria.
    - Inducida por fármacos o toxinas.
    - Asociada a uno de los siguientes:
    o Enfermedad del tejido conectivo.
    o Infección por VIH.
    o Hipertensión portal.
    o Enfermedad cardiaca congénita con derivación sistémica-pulmonar simple (comunicación interauricular, comunicación interventricular, conducto arterial patente) con hipertensión pulmonar persistente documentada por un cateterismo cardiaco derecho ≥1 año después de la reparación quirúrgica
    5. Diagnóstico de HAP confirmado mediante una evaluación hemodinámica en reposo, evaluada en las 5 semanas previas a la aleatorización:
    - Presión arterial pulmonar media 25 mmHg; Y
    - Presión en cuña de la arteria pulmonar o presión diastólica final del ventrículo izquierdo ≤15 mmHg; Y
    - RVP 3 unidades Wood (es decir, ≥240 dyn∙s∙cm−5)
    6. Prueba de vasorreactividad negativa en HAP idiopática, hereditaria o inducida por fármacos o toxinas.
    7. Sin antecedentes de tratamiento específico de HAP o recibiendo actualmente una dosis estable de ARE o iFDE-5 como monoterapia durante al menos 3 meses antes del CCD (cateterismo cardiaco derecho) basal, dentro de las siguientes dosis previamente especificadas:
    - Bosentán: 250 mg de dosis diaria total.
    - Macitentán: 10 mg de dosis diaria total.
    - Ambrisentán: 10 mg de dosis diaria total.
    - Sildenafilo: 60-120 mg de dosis diaria total.
    - Tadalafilo: 40 mg de dosis diaria total.
    - Vardenafilo: 10 mg de dosis diaria total.
    8. Paciente capaz de realizar el test de la marcha de los 6 minutos con una distancia mínima de 100 m y máxima de 450 m en la selección.
    9. Una mujer en edad fértil solo se considera apta si se cumple lo siguiente:
    - Prueba de embarazo en suero negativa en la selección y prueba de embarazo en orina negativa en la aleatorización.
    - Acuerdo para someterse a pruebas mensuales de embarazo en orina durante el estudio y hasta por lo menos 30 días después de la interrupción del tratamiento del estudio.
    - Acuerdo para seguir el programa anticonceptivo desde la selección y hasta por lo menos 30 días después de la interrupción del tratamiento del estudio.
    E.4Principal exclusion criteria
    PAH treatments:
    1. Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form of prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused routes) in the 3-month period prior to start of treatment.
    2. Treatment with combination therapy of ERA and PDE-5i in the 3-month period prior to start of treatment or history of intolerance to ERA and PDE-5i combination therapy.
    3. Hypersensitivity to any of the study treatments or any excipient of their formulations.

    Other therapies:
    4. Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer (e.g., rifabutin, rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort) in the 1-month period prior to start of treatment.
    5. Treatment with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) in the 1-month period prior to start of treatment.
    6. Treatment with doxazosin.
    7. Treatment with any form of organic nitrate, either regularly or intermittently
    8. Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start of treatment.
    9. Treatment with another investigational drug in the 3-month period prior to start of treatment.

    Medical history/current medical conditions:
    10. Body mass index (BMI) > 40 kg/m2 at Screening.
    11. Known presence of three or more of the following risk factors for heart failure with preserved ejection fraction at Screening:
    - BMI > 30 kg/m2.
    − Diabetes mellitus of any type.
    − Essential hypertension (even if well controlled).
    − Coronary artery disease, i.e., any of the following:
    o History of stable angina, or
    o Known more than 50% stenosis in a coronary artery, or
    o History of myocardial infarction, or
    o History of or planned coronary artery bypass grafting and/or coronary artery stenting.
    12. Known presence of moderate or severe obstructive lung disease (forced expiratory volume in 1 second [FEV1] / forced vital capacity [FVC] < 70%; and FEV1 < 65% of predicted after bronchodilator administration) any time prior to Screening.
    13. Known presence of moderate or severe restrictive lung disease (total lung capacity or FVC < 60% of normal predicted value) any time prior to Screening.
    14. Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive left-sided cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction; or left ventricular outflow obstruction.
    15. Known permanent atrial fibrillation.
    16. Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).
    17. Documented pulmonary veno-occlusive disease.

    Criteria linked to macitentan/tadalafil use:
    18. Hemoglobin < 100 g/L (<10 g/dL) at Screening.
    19. Known severe hepatic impairment defined as Child Pugh Score C or a Model for End-Stage Liver Disease (MELD) score ≥ 19.
    20. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 × upper limit of normal (ULN) at Screening.
    21. Severe renal impairment (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation [Levey 2009] calculated creatinine clearance < 30 mL/min) at Screening.
    22. Systemic hypotension (systolic blood pressure [SBP] < 90 or diastolic blood pressure [DBP] < 50 mmHg) at Screening or Randomization.
    23. Systemic hypertension (SBP > 160 or DBP > 100 mmHg) at Screening.
    24. Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last 26 weeks prior to Screening.
    25. Known bleeding disorder.
    26. Loss of vision in one or both eyes because of non-arteritic anterior ischemic optic neuropathy, regardless of whether or not this episode was in connection with previous PDE-5i treatment.
    27. Hereditary degenerative retinal disorders, including retinitis pigmentosa.
    28. History of priapism, conditions that predispose to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia) or anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease).

    General restrictions:
    29. Difficulty swallowing large pills/tablets that would interfere with the ability to comply with study treatment regimen.
    30. Any planned surgical intervention (including organ transplant) during the double-blind treatment period, except minor interventions.
    31. Exercise training program for cardiopulmonary rehabilitation in the 12-week period prior to Start of treatment, or planned to be started during the study.
    32. Pregnant, planning to become pregnant or lactating.
    33. Any known factor or disease that might interfere with treatment adherence, study assessments, study conduct, or interpretation of the results as judged by the investigator (e.g., drug or alcohol dependence, psychiatric disease, use of walking aids, etc.).
    34. Known concomitant life-threatening disease with a life expectancy < 12 months.
    Tratamientos para la HAP:
    1. Tratamiento con un estimulador soluble de guanilato ciclasa, L-arginina, cualquier forma de prostanoide o agonista del receptor de prostaciclina (lo que incluye la administración oral, inhalada o infundida) en los 3 meses anteriores al inicio del tratamiento.
    2. Tratamiento con terapia combinada de ARE e iFDE-5 en los 3 meses anteriores al inicio del tratamiento o antecedentes de intolerancia a la terapia combinada de ARE e iFDE-5.
    3. Hipersensibilidad a cualquiera de los tratamientos del estudio o a cualquier excipiente de sus formulaciones.
    Otros tratamientos:
    4. Tratamiento con un inductor fuerte del citocromo P450 (CYP) 3A4 (por ejemplo, rifabutina, rifampina, rifampicina, rifapentina, carbamazepina, fenobarbital, fenitoína o hierba de San Juan) en el periodo de 1 mes antes del inicio del tratamiento.
    5. Tratamiento con un inhibidor fuerte del CYP3A4 (por ejemplo, ketoconazol, itraconazol, voriconazol, claritromicina, telitromicina, nefazodona, ritonavir o saquinavir) en el periodo de 1 mes antes del inicio del tratamiento.
    6. Tratamiento con doxazosina.
    7. Tratamiento con cualquier forma de nitrato orgánico, ya sea habitual o intermitente.
    8. Tratamiento diurético iniciado o dosis modificada en el plazo de 1 semana antes del CCD o el inicio del tratamiento.
    9. Tratamiento con otro fármaco en investigación en el periodo de 3 meses antes del inicio del tratamiento.
    Historial médico/afecciones médicas actuales:
    10. Índice de masa corporal (IMC) >40 kg/m2 en la selección.
    11. Presencia conocida de tres o más de los siguientes factores de riesgo de insuficiencia cardiaca con fracción de eyección preservada en la selección:
    - IMC >30 kg/m2.
    - Diabetes mellitus de cualquier tipo.
    - Hipertensión esencial (incluso si está bien controlada).
    - Enfermedad de las arterias coronarias, es decir, cualquiera de las siguientes:
    o Antecedentes de angina estable; o
    o Estenosis conocida de más del 50 % en una arteria coronaria; o
    o Antecedentes de infarto de miocardio; o
    o Antecedentes o planes de injerto de bypass de la arteria coronaria o colocación de stents en la arteria coronaria.
    12. Presencia conocida de enfermedad pulmonar obstructiva moderada o grave (volumen espiratorio forzado en 1 segundo) [VEF1]/capacidad vital forzada [CVF] <70 % y VEF1 <65 % de lo pronosticado después de la administración de un broncodilatador) en cualquier momento antes de la selección.
    13. Presencia conocida de enfermedad pulmonar restrictiva moderada o grave (capacidad pulmonar total o CVF <60 % del valor normal pronosticado) en cualquier momento antes de la selección.
    14. Enfermedad valvular aórtica o mitral clínicamente significativa, constricción pericárdica, miocardiopatía izquierda restrictiva o congestiva, arritmias cardiacas potencialmente mortales, disfunción ventricular izquierda significativa u obstrucción del flujo ventricular izquierdo.
    15. Fibrilación auricular permanente conocida.
    16. Enfermedad tiroidea descontrolada conocida o presunta (hipotiroidismo o hipertiroidismo).
    17. Enfermedad venooclusiva pulmonar documentada.
    Criterios asociados al uso de macitentán/tadalafilo:
    18. Hemoglobina <100 g/l (<10 g/dl) en la selección.
    19. Insuficiencia hepática grave conocida, definida como una puntuación de Child-Pugh de grado C, o una puntuación del modelo de enfermedad hepática terminal (MELD) ≥19.
    20. Aspartato aminotransferasa o alanina aminotransferasa en suero >1,5  límite superior de la normalidad en la selección.
    21. Insuficiencia renal grave (aclaramiento de creatinina calculado mediante la ecuación de Chronic Kidney Disease Epidemiology Collaboration 2009 [Levey 2009] <30 ml/min) en la selección.
    22. Hipotensión sistémica (presión arterial sistólica [PAS] <90 mmHg o presión arterial diastólica [PAD] <50 mmHg) en la selección o la aleatorización.
    23. Hipertensión sistémica (PAS >160 mmHg o PAD> 100 mmHg) en la selección.
    24. Infarto agudo de miocardio o accidente cerebrovascular (por ejemplo, ictus) en las 26 semanas anteriores a la selección.
    25. Trastorno hemorrágico conocido.
    26. Pérdida de visión en uno o ambos ojos por una neuropatía óptica isquémica anterior no arterítica, independientemente de que este episodio esté o no relacionado con el tratamiento previo con iFDE-5.
    27. Trastornos degenerativos hereditarios de la retina, incluida la retinitis pigmentaria.
    28. Antecedentes de priapismo, afecciones que predispongan al priapismo (por ejemplo, anemia drepanocítica, mieloma múltiple o leucemia) o deformación anatómica del pene (por ejemplo, angulación, fibrosis cavernosa o enfermedad de Peyronie).
    Restricciones generales:
    Para más información, consultar página 11 del resumen del protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    • Change in PVR expressed as the ratio of the geometric means of end of double blind treatment (EDBT) to baseline.
    • Cambio en la RVP expresada como la relación entre la media geométrica del FTDC y el momento basal.
    E.5.1.1Timepoint(s) of evaluation of this end point
    end of double blind treatment (EDBT)
    Fin de tratamiento doble ciego (FTDC)
    E.5.2Secondary end point(s)
    • Change from baseline to EDBT in 6-minute walk distance.
    • Change from baseline to EDBT in PAH-SYMPACT™ Cardiopulmonary symptom domain score.
    • Change from baseline to EDBT in PAH-SYMPACT™ Cardiovascular symptom domain score.
    • Change from baseline to EDBT in PAH-SYMPACT™ Physical impact domain score.
    • Change from baseline to EDBT in PAH-SYMPACT™ Cognitive/emotional impact domain score.
    • Proportion of subjects with absence of worsening in WHO FC from baseline to EDBT.
    • Cambio desde el momento basal hasta el FTDC en la distancia del test de la marcha de 6 minutos.
    • Cambio desde el momento basal hasta el FTDC en la puntuación del dominio de síntomas cardiopulmonares de PAH-SYMPACT™.
    • Cambio desde el momento basal hasta el FTDC en la puntuación del dominio de síntomas cardiovasculares de PAH-SYMPACT™.
    • Cambio desde el momento basal hasta el FTDC en la puntuación del dominio de impacto físico de PAH-SYMPACT™.
    • Cambio desde el momento basal hasta el FTDC en la puntuación del dominio de impacto cognitivo/emocional de PAH-SYMPACT™.
    • Proporción de pacientes con ausencia de empeoramiento en la CF de la OMS desde el momento basal hasta el FTDC.
    E.5.2.1Timepoint(s) of evaluation of this end point
    end of double blind treatment (EDBT)
    Fin de tratamiento doble ciego (FTDC)
    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 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 Yes
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    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 Yes
    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) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    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
    Australia
    Brazil
    Bulgaria
    Canada
    China
    Czech Republic
    Germany
    Hungary
    Italy
    Japan
    Malaysia
    Mexico
    Poland
    Russian Federation
    Spain
    Taiwan
    Turkey
    United States
    E.8.7Trial 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
    LVLS
    Última visita último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    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: 128
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 42
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 76
    F.4.2.2In the whole clinical trial 170
    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)
    After the subjects' study completion or premature withdrawal from the study, whichever applies, the investigator/delegate will explain to the subjects what treatment(s)/medical care is necessary and available according to local regulations.
    Una vez que el sujeto haya completado el estudio o se haya retirado prematuramente del estudio, lo que corresponda, el investigador/delegado explicará a los sujetos qué tratamiento(s)/atención médica es necesario y está disponible de acuerdo con las regulaciones locales.
    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 Decision2019-08-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-17
    P. End of Trial
    P.End of Trial StatusOngoing
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA