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    Summary
    EudraCT Number:2019-002533-11
    Sponsor's Protocol Code Number:UNISUS
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-15
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-002533-11
    A.3Full title of the trial
    A Phase 3, Prospective, Multicenter, Double-blind, Double-dummy, Randomized, Active-controlled, Parallel-group, Group-sequential, Adaptive, Event-driven Study to Compare Efficacy, Safety, and Tolerability of Macitentan 75 mg Versus Macitentan 10 mg in Patients with Pulmonary Arterial Hypertension, Followed by an Open-label Treatment Period With Macitentan 75 mg
    Uno studio multicentrico di Fase III, prospettico, in doppio cieco, con doppio placebo, randomizzato, con controllo attivo, a gruppi paralleli, a gruppi sequenziali, con disegno adattivo, guidato dagli eventi, per confrontare l’efficacia, la sicurezza e la tollerabilità di Macitentan 75 mg rispetto a Macitentan 10 mg in pazienti affetti da ipertensione arteriosa polmonare, con successivo periodo di trattamento in aperto con Macitentan 75 mg
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized Study to Compare Efficacy, Safety, and Tolerability of Macitentan 75 mg Versus Macitentan 10 mg in Patients with Pulmonary Arterial Hypertension, Followed by an Open-label Treatment Period with Macitentan 75 mg.
    Studio randomizzato per confrontare l’efficacia, la sicurezza e la tollerabilità di Macitentan 75 mg rispetto a Macitentan 10 mg in pazienti affetti da ipertensione arteriosa polmonare, con successivo periodo di trattamento in aperto con Macitentan 75 mg.
    A.3.2Name or abbreviated title of the trial where available
    UNISUS
    UNISUS
    A.4.1Sponsor's protocol code numberUNISUS
    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 organisationJanssen-Cilag International NV
    B.5.2Functional name of contact pointClinical Registry group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 CM
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031715242166
    B.5.5Fax number0031715242110
    B.5.6E-mailClinicalTrialsEU@its.jnj.com
    D. IMP Identification
    D.IMP: 1
    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 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 tablets
    D.3.2Product code [JNJ-67896062 / 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 codeMACITENTAN
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 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.3.1Product namemacitentan tablets
    D.3.2Product code [JNJ-67896062 / 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 codeMACITENTAN
    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 number75
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 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.3.1Product namemacitentan tablets
    D.3.2Product code [JNJ-67896062 / 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 codeMACITENTAN
    D.3.9.4EV Substance CodeSUB89247
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number37500
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 placeboFilm-coated tablet
    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
    Ipertensione arteriosa polmonare
    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
    L'ipertensione arteriosa polmonare (IAP) è una condizione in cui la pressione dei vasi sanguigni che portano il sangue ai polmoni (arterie polmonari) è più alta del normale
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    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 demonstrate superiority of macitentan 75 mg in prolonging the time to the first CEC-adjudicated morbidity or mortality (M/M) event in partecipant with symptomatic pulmonary arterial hypertension (PAH) compared to macitentan 10 mg.
    Dimostrare la superiorità di macitentan 75 mg, rispetto a macitentan 10 mg, nel prolungare il tempo al primo evento di morbilità o mortalità (M/M) valutato da una Central Event Committee (CEC) in soggetti con ipertensione arteriosa polmonare (PAH) sintomatica.
    E.2.2Secondary objectives of the trial
    - To demonstrate that macitentan 75 mg improves exercise capacity compared to macitentan 10 mg;
    - To demonstrate that macitentan 75 mg prolongs the time to death or hospitalization due to PAH (adjudicated by an independent CEC) compared to macitentan 10 mg;
    - To assess the effect of macitentan 75 mg compared to macitentan 10 mg on PAH symptoms on participants' life;
    - To assess the effect on prolongation of the CEC-adjudicated time to death of macitentan 75 mg compared to macitentan 10 mg.
    - Dimostrare che macitentan 75 mg migliora la capacità di sforzo rispetto a macitentan 10 mg;
    - Dimostrare che macitentan 75 mg prolunga il tempo al decesso o al ricovero dovuto a PAH (valutato da un CEC indipendente) rispetto a macitentan 10 mg;
    - Valutare l’effetto di macitentan 75 mg rispetto a macitentan 10 mg sui sintomi della PAH che comportano un impatto sulla vita dei soggetti;
    - Valutare l’effetto di macitentan 75 mg sul prolungamento del tempo al decesso rispetto a macitentan 10 mg; valutazione fatta dalla Central Event Committee (CEC)
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: -One "PK/PD sub-study" (AC-055-315 Protocol): To evaluate the pharmacokinetics (PK) of macitentan and its metabolite ACT-132577 and the Pharmacodynamic (PD) profile of endothelin-1 (ET- 1) levels in response to macitentan treatment in patients with PAH (subset of participants);
    - One "cardiac remodeling sub-study" (AC-055-315 Protocol): To evaluate the effect of macitentan 75 mg on right ventricular properties compared to macitentan 10 mg (subset of participants);
    - One "hemodynamic sub-study" (AC-055-315 Protocol): To evaluate effect of macitentan 75 mg on hemodynamic measures compared to macitentan 10 mg (subset of participants).

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: - Sottostudio di farmacocinetica (PK)/Famacodinamica (PD) (Protocollo AC-055-315): valutare la farmacocinetica (PK) di macitentan e del suo metabolita ACT-132577 e il profilo farmacodinamico (PD) dei livelli di endotelina-1 (ET-1) in risposta al trattamento con macitentan in pazienti con PAH (sottogruppo di partecipanti);
    - Sottostudio sul rimodellamento cardiaco (Protocollo AC-055-315): Valutare l’effetto di macitentan 75 mg, rispetto a macitentan 10 mg, sulle caratteristiche del ventricolo destro (sottogruppo di soggetti);
    - Sottostudio di emodinamica (Protocollo AC-055-315): Valutare l’effetto di macitentan 75 mg sui parametri emodinamici rispetto a macitentan 10 mg (sottogruppo di soggetti).
    E.3Principal inclusion criteria
    1. Restricted population: =maj18 and =min 75 years of age. Target population: = maj 18 years of age.
    2. Restricted population: Symptomatic PAH in WHO FC II or III Target population: Symptomatic PAH in WHO FC II, III, or IV
    3. Must sign an ICF (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
    4. Restricted population: PAH subtype falling in one of the below classifications:- Idiopathic - Heritable - Drug- or toxin-induced - Related to: *Connective tissue disease, * HIV infection, * Congenital heart disease with simple systemic-to-pulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus) with persistent PH documented by an RHC = 1 year after surgical repair. Target populationa: PAH subtype falling in one of the below classifications:- Idiopathic- Heritable- Drug- or toxin-induced- Related to:*Connective tissue disease,*HIV infection,*Portal hypertension*Congenital heart disease with simple systemic-topulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus) with persistent PH documented by an RHC = 1 year after surgical repair.
    5. PAH diagnosis confirmed by hemodynamic evaluation at rest at any time prior to Screening: - Mean pulmonary artery pressure (mPAP) > 20 mmHg, AND - Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) =min 15 mmHg, AND - PVR =maj 3 Wood Units (ie, = maj 240 dyn·sec·cm-5).
    6. Negative vasoreactivity test in idiopathic, heritable, and drug/toxininduced PAH. Patients for whom no vasoreactivity test was performed at diagnosis and currently treated with PAH therapy for more than 3 months, must have a confirmatory PAH diagnosis documented by hemodynamic evaluation at least 3 months after introduction of their PAH therapy.
    7. Able to perform the 6MWT with a minimum distance of 50 m and maximum distance of 440 m at Screening.
    8. Patients already receiving PAH therapies (mono or combination therapies) should be on a stable regimen for at least 3 months prior to screening visit and planned to be: - If on ERA therapy: discontinued at randomization or start of run-in (ie, last dose of ERA taken the day before initiating study intervention), - If on PAH therapy other than ERA: maintained on top of the study intervention.
    9. Must sign a separate informed consent form (or their legally acceptable representative must sign) if he or she agrees to provide optional samples for biomarker research (where local regulations permit). Refusal to give consent for the optional biomarker research samples does not exclude a participant from participation in the study.
    10. A woman of childbearing potential must have a negative highly sensitive serum (ß-human chorionic gonadotropin [ß-hCG]) test at Screening and a negative urine pregnancy test prior to receiving their first dose of study intervention (i.e. either at beginning of the run-in period or prior to randomization [see Section 4.1]).
    11. A woman must be (as defined in Appendix 6) a) Not of childbearing potential, b) Of childbearing potential and - Practicing a highly effective, preferably user-independent method of contraception (failure rate of < 1% per year when used consistently and correctly) and agrees to remain on a highly effective method while receiving study intervention and until 30 days after last dose - the end of relevant systemic exposure. Examples of highly effective methods of contraception are located in Appendix 6.
    12. Willing and able to adhere to the lifestyle restrictions specified in this protocol.
    1. Popolazione ristretta: età =mag 18 anni e = min 75 anni. Popolazione target : età = mag 18 anni .
    2. Popolazione ristretta: PAH sintomatica in WHO FC II o III Popolazione targeta: PAH sintomatica in WHO FC II, III o IV
    3. I soggetti (o i relativi rappresentanti legali autorizzati) devono firmare un ICF in cui indicano di aver compreso lo scopo dello studio e le relative procedure e di essere intenzionati a parteciparvi.
    4. Popolazione ristretta: Sottotipo PAH rientrante in una delle seguenti categorie:• Idiopatica•Ereditaria•Indotta da farmaco o tossina •Correlata a: - malattia del tessuto connettivo, - infezione da HIV, - malattia cardiaca congenita con shunt sistemico-polmonare semplice (difetto del setto atriale, difetto del setto ventricolare, dotto arterioso pervio) con PH persistente, documentata da RHC = 1 anno dopo la riparazione chirurgica.
    Popolazione target: Sottotipo PAH rientrante in una delle seguenti categorie:•Idiopatica•Ereditaria•Indotta da farmaco o tossina•Correlata a:- malattia del tessuto connettivo,- infezione da HIV,- ipertensione portale,- malattia cardiaca congenita con shunt sistemico-polmonare semplice (difetto del setto atriale, difetto del setto ventricolare, dotto arterioso pervio) con PH persistente, documentata da RHC = mag 1 anno dopo la riparazione chirurgica.
    5. Diagnosi di PAH confermata mediante valutazione emodinamica a riposo in qualsiasi momento prima dello screening:• pressione arteriosa polmonare media (mPAP) > 20 mmHg, E • pressione di incuneamento dell'arteria polmonare (PAWP) o pressione telediastolica ventricolare sinistra (LVEDP)min =min 15 mmHg, E • RVP 3 unità Wood (ossia =mag 240 dyn·sec·cm-5)
    6. Test di vasoreattività negativo in caso di PAH idiopatica, ereditaria e indotta da farmaco/tossina. I pazienti per i quali non è stato eseguito un test di vasoreattività al momento della diagnosi e attualmente trattati con terapia per la PAH per più di 3 mesi, devono avere una diagnosi di PAH confermata e documentata dalla valutazione emodinamica almeno 3 mesi dopo l'introduzione della loro terapia per PAH.
    7. Soggetto in grado di sostenere, allo screening, un test 6MWT con una distanza compresa tra un minimo di 50 m e un massimo di 440 m.
    8. I pazienti già in trattamento per PAH (monoterapie o terapie in associazione) devono mantenere un regime stabile per almeno 3 mesi prima della visita di screening e per tale regime si deve prevedere:
    • in caso di trattamento con ERA: interruzione al momento della randomizzazione o all’inizio del run-in (ossia l’ultima dose di ERA deve essere assunta il giorno precedente all’inizio del trattamento dello studio),
    • in caso di trattamento con terapia per PAH diversa da ERA: mantenimento in aggiunta al trattamento dello studio.
    9. Se acconsente a fornire campioni facoltativi destinati alla ricerca sui biomarcatori (ove consentito dalla normativa locale), il soggetto (o il rappresentante legale autorizzato) deve firmare un modulo di consenso informato separato. Il mancato consenso al prelievo di campioni facoltativi destinati alla ricerca sui biomarcatori non esclude i soggetti dalla partecipazione allo studio.
    10. Al momento dello screening, le donne potenzialmente fertili devono risultare negative a un test di gravidanza altamente sensibile sul siero.
    11. Le donne devono (secondo quanto definito nell’Appendice 6) a. non essere potenzialmente fertili, oppure b. essere potenzialmente fertili e - utilizzare un metodo contraccettivo altamente efficace, preferibilmente indipendente dall’utilizzatore e accettare di utilizzare un metodo altamente efficace durante l’assunzione del trattamento dello studio e per i 30 giorni successivi all’ultima dose - la conclusione dell’esposizione sistemica rilevante.
    Alcuni esempi di metodi contraccettivi altamente efficaci sono indicati all’Appendice 6.
    12. Volontà e capacità di conformarsi alle limitazioni relative allo stile di vita specificate in questo protocollo.
    E.4Principal exclusion criteria
    1. Restricted population only: Subjects not yet exposed to any PAH treatment at Screening.
    2. Restricted population only: Treatment with prostanoids at Screening. Prostacyclin receptor agonists are allowed, if on stable dose for at least 3 months.
    3. Does meet any of the following run-in failure criteria:- Study intervention compliance < 80%, - Central laboratory results showing a decrease in hemoglobin by > 20 g/L from Screening or hemoglobin < 100 g/L or need for transfusion not explained by other confounding factors,
    - Significant fluid retention as evidenced by one of the following: *Administration of iv diuretics due to fluid retention, *Addition of high potency thiazide diuretic (metolazone, indapamide), =maj100% increase in loop diuretic to a total oral dose = 120 mg of furosemide equivalents/day, *Increase in body weight by = maj 5% or = maj 5 kg from the value at the start of the run-in period.
    - The investigator considers that for safety reasons or tolerability reasons (eg, AE) it is in the best interests of the participant to discontinue the study.
    Subjects who are run-in failures per the criteria described above will be considered screen failures (see Section 5.4).
    4. Treatment with a strong CYP3A4 inducer within 1 month prior to Baseline.
    5. Treatment with a strong CYP3A4 inhibitor or a moderate dual CYP3A4/CYP2C9 inhibitor, or co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors in the 1-month period prior to baseline.
    6. Treatment with a soluble guanylate cyclase stimulator within 1 month prior to Baseline, unless results of Drug-Drug Interaction (DDI) study allow its concomitant use with macitentan 75 mg during the course of the study, as communicated by the sponsor.
    7. For participants involved in the cardiac remodeling and/or hemodynamic substudies only: Diuretic treatment initiated or dose changed within 1 week prior to the MRI or RHC assessment.
    8. Known presence of three or more of the following risk factors for heart failure with preserved ejection fraction at Screening, based on records that confirm documented medical history: - Body mass index (BMI) > 30 kg/m2, - Diabetes mellitus of any type, - Essential hypertension (even if well controlled),
    - Coronary artery disease, ie, any of the following: *History of stable angina, or *Known more than 50% stenosis in a coronary artery, or *History of myocardial infarction, or *History of or planned coronary artery bypass grafting and/or coronary artery stenting.
    9. Known presence of moderate or severe obstructive lung disease as documented by a spirometry test performed within 1 year at any time prior to Screening.
    10. Known presence of moderate or severe restrictive lung disease as documented by a spirometry test performed within 1 year at any time prior to Screening.
    11. Significant un repaired structural valvular heart disease (ie, moderate or severe aortic or mitral stenosis or regurgitation); pericardial constriction; restrictive or congestive left-sided cardiomyopathy; life threatening cardiac arrhythmias; significant left ventricular dysfunction; or left ventricular outflow obstruction.
    12. Permanent atrial fibrillation or atrial flutter, in the opinion of the investigator.
    13. Documented pulmonary veno-occlusive disease.
    14. Known moderate to severe hepatic impairment, defined as Child- Pugh Class B or C (see Appendix 5), based on records that confirm documented medical history.
    15. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)> 1.5 X upper limit of normal (ULN) at Screening.
    16. Hemoglobin < 100 g/L (< 10 g/dL) at Screening.
    17. Severe renal impairment as defined with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 at screening
    For other criteria, please refer to protocol
    1. Solo per la popolazione ristretta : soggetti che al momento dello screening non siano mai stati esposti a trattamenti per PAH.
    2. Solo per la popolazione ristretta: trattamento con prostanoidi al momento dello screening. Gli agonisti del recettore della prostaciclina sono consentiti, purché somministrati con dose stabile da almeno 3 mesi.
    3. Soddisfa uno dei seguenti criteri di insuccesso durante il run-in: • Compliance al trattamento dello studio < 80% •Riduzione dell’emoglobina in misura > 20 g/L rispetto allo screening, secondo i risultati forniti dal laboratorio centrale, livelli di emoglobina < 100 g/L oppure necessità di trasfusione non giustificata da altri fattori confondenti, • Ritenzione di liquidi clinicamente significativa dimostrata mediante: - somministrazione di diuretici per via endovenosa a causa di ritenzione di liquidi, -aggiunta di un diuretico tiazidico a elevata potenza, incremento in misura = mag100% del diuretico dell'ansa per una dose totale = mag 120 mg di equivalenti di furosemide/giorno per via orale, -aumento del peso corporeo in misura = mag 5% o= mag 5 kg rispetto al valore rilevato all’inizio del periodo di run-in
    I soggetti che soddisfano i criteri di insuccesso di cui sopra saranno considerati come screen failures.
    4. Trattamento con un potente induttore del CYP3A4 nel mese precedente il basale.
    5. Trattamento con un forte inibitore del CYP3A4 o un moderato doppio inibitore del CYP3A4 / CYP2C9 o co-somministrazione di una combinazione di moderati CYP3A4 e moderati inibitori del CYP2C9 nel periodo di 1 mese prima del basale.
    6. Trattamento con uno stimolatore solubile della guanilato ciclasi nel mese precedente il basale, a meno che i risultati dello studio di interazione farmacologica (DDI) ne consentano l’uso concomitante con macitentan 75 mg nel corso dello studio, secondo quanto comunicato dallo sponsor.
    7. Solo per i partecipanti coinvolti nel sottostudio sul rimodellamento cardiaco e/o di emodinamica: Inizio o variazione di dosaggio di un trattamento diuretico nella settimana precedente la valutazione MRI o RHC.
    8. Presenza nota di tre o più dei seguenti fattori di rischio di insufficienza cardiaca con frazione di eiezione preservata al momento dello screening, secondo cartelle cliniche fornite per documentazione dell’anamnesi: •Indice di massa corporea (IMC) > 30 kg/m2, •Diabete mellito di qualsiasi tipo, •Ipertensione essenziale, • Malattia coronarica, ad es. una delle seguenti: -anamnesi di angina stabile, o -presenza nota di stenosi superiore al 50% in un’arteria coronarica, o - anamnesi di infarto miocardico, o - anamnesi o previsione di innesto di bypass di un’arteria coronarica e/o stent coronarico.
    9. Presenza nota di malattia polmonare ostruttiva moderata o severa, come documentata da spirometria entro 1 anno prima dello screening.
    10. Presenza nota di malattia polmonare restrittiva moderata o severa, come documentata da spirometria entro 1 anno prima dello screening.
    11. Valvulopatia cardiaca strutturale senza avvenuta riparazione e clinicamente significativa; costrizione pericardica; cardiomiopatia sul lato sinistro, restrittiva o congestizia; aritmia cardiaca potenzialmente letale; disfunzione ventricolare sinistra significativa; oppure ostruzione dell’efflusso ventricolare sinistro.
    12. Fibrillazione o flutter atriale permanenti, in base al giudizio dello sperimentatore.
    13. Malattia veno-occlusiva polmonare documentata.
    14. Compromissione epatica nota, da moderata a grave, definita come di classe B o C Child-Pugh , secondo cartelle cliniche a conferma di un’anamnesi documentata.
    15. Aspartato aminotransferasi e/o alanina aminotransferasi sieriche > 1,5 volte il limite superiore della norma (ULN) allo screening.
    16. Emoglobina < 100 g/L (<10 g/dL) allo screening.
    17. Grave compromissione renale con un rapporto di filtrazione glomerulare stimata < 30 mL/min/1.73m2 allo screening.
    Per gli altri criteri fare riferimento al protocollo
    E.5 End points
    E.5.1Primary end point(s)
    • Time to first CEC-adjudicated M/M event on-treatment (ie, up to 7 days after the last dose of double-blind (DB) study treatment), defined as time from baseline to the first of the following events:
    - All-cause death, including deaths caused by an on-treatment AE, that occur within 4 weeks of study DB treatment discontinuation
    - Non-planned PAH-related hospitalization (including for worsening of PAH, atrial septostomy, lung transplantation with or without heart transplantation, or initiation of parenteral prostacyclins)
    - PAH-related disease progression, defined as (both criteria must be satisfied):
    o Deterioration by at least 15% in exercise capacity, as measured by the 6-minute walk distance (6MWD), from baseline, confirmed by two 6MWD test performed on separate days within 2 weeks of each other
    o Initiation of additional PAH therapy or Worsening of WHO FC
    • Tempo al primo evento M/M valutato da CEC che si verifica durante il trattamento (ossia fino a 7 giorni dopo l’assunzione dell’ultima dose di trattamento dello studio in doppio cieco [DB]), inteso come arco di tempo compreso tra il basale e la prima insorgenza di uno dei seguenti eventi:
    - decesso per qualsiasi causa, inclusi i decessi causati da un AE durante il trattamento, che avviene entro le 4 settimane successive all’interruzione del trattamento dello studio in doppio cieco
    - ricovero in ospedale correlato alla PAH non pianificato (anche per un peggioramento della PAH, per settostomia atriale, trapianto polmonare con o senza trapianto cardiaco oppure per l’inizio di un trattamento con prostacicline per via parenterale)
    - progressione della malattia, intesa come (entrambi i criteri devono essere soddisfatti):
    o peggioramento almeno del 15% rispetto al basale della capacità di esercizio, misurata come la distanza percorsa a piedi in 6 minuti (6MWD), confermata effettuando 2 test 6MWD in giorni separati a una distanza massima di 2 settimane l’uno dall’altro.
    o Inizio di una terapia aggiuntiva della PAH o peggioramento della FC WHO
    E.5.1.1Timepoint(s) of evaluation of this end point
    At each study visits, monthly and at any time in case of event occurrence, until 217 M/M events are reached
    Ad ogni visita di studio, mensilmente e in qualsiasi momento in caso si verifichino eventi, fino al raggiungimento di 217 eventi M/M
    E.5.2Secondary end point(s)
    • Change from baseline to Week 24 in 6MWD; Time to first occurrence of either death due to PAH or hospitalization for PAH, CEC adjudicated event on-treatment (ie, up to 7 days after the last dose of DB study treatment), as defined hereafter:
    - Death due to PAH, including deaths caused by on-treatment AE that occur within 4 weeks of study DB treatment discontinuation
    OR
    - Non-planned PAH-related hospitalization; • Change from baseline to Week 24 in PAH-SYMPACT:
    - Cardiopulmonary symptom domain score
    - Cardiovascular symptom domain score; Time to death occurring between baseline and end of double-blind treatment (EDBT) period as defined hereafter:
    - All-cause death, including deaths caused by AE during the DB treatment period that occur within 4 weeks of study DB treatment discontinuation
    • Variazione nel test 6MWD tra il basale e la settimana 24; Tempo alla prima occorrenza di decesso o ricovero dovuti a PAH, inteso come evento valutato CEC che si verifica durante il trattamento (ossia fino a 7 giorni dopo l’assunzione dell’ultima dose di trattamento dello studio in DB), secondo la seguente definizione:
    - Decesso dovuto a PAH, inclusi i decessi causati da un AE durante il trattamento, che avviene entro le 4 settimane successive all’interruzione del trattamento dello studio in DB
    OPPURE
    - Ricovero non programmato correlato a PAH; • Variazione tra il basale e la settimana 24 nel questionario sui sintomi e l’impatto della PAH (PAH-SYMPACT):
    - Punteggio nell’ambito dei sintomi cardiopolmonari
    - Punteggio nell’ambito dei sintomi cardiovascolari; Tempo al decesso nel periodo compreso tra il basale e la fine del periodo di trattamento in doppio cieco (EDBT) secondo la seguente definizione:
    - decesso per qualsiasi causa, inclusi i decessi causati da un AE verificatosi durante il periodo di trattamento in doppio cieco, entrole 4 settimane successive all’interruzione del trattamento in doppio cieco
    E.5.2.1Timepoint(s) of evaluation of this end point
    Screening, Day 1, Month 3, and all scheduled visits thereafter until EDBT or anytime in case of event, with the exception of PAH-SYMPACT; Screening, Day 1, Month 3, and all scheduled visits thereafter until EDBT or anytime in case of event, with the exception of PAH-SYMPACT; Screening, Day 1, Month 3, and all scheduled visits thereafter until EDBT or anytime in case of event, with the exception of PAH-SYMPACT; Screening, Day 1, Month 3, and all scheduled visits thereafter until EDBT or anytime in case of event, with the exception of PAH-SYMPACT
    Screening, giorno 1, mese 3 e tutte le visite programmate da allora in poi fino a EDBT o in qualsiasi momento in caso di evento, ad eccezione di PAH-SYMPACT; Screening, giorno 1, mese 3 e tutte le visite programmate da allora in poi fino a EDBT o in qualsiasi momento in caso di evento, ad eccezione di PAH-SYMPACT; Screening, giorno 1, mese 3 e tutte le visite programmate da allora in poi fino a EDBT o in qualsiasi momento in caso di evento, ad eccezione di PAH-SYMPACT; Screening, giorno 1, mese 3 e tutte le visite programmate da allora in poi fino a EDBT o in qualsiasi momento in caso di evento, ad eccezione di PAH-SYMPACT
    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 Yes
    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 Yes
    E.8.1.7.1Other trial design description
    singolo braccio dopo il periodo di doppio cieco
    single arm after the Double Blind period
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    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 concerned5
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Austria
    Belarus
    Belgium
    Brazil
    Canada
    China
    Colombia
    Czechia
    Denmark
    France
    Germany
    Hungary
    Israel
    Italy
    Japan
    Korea, Republic of
    Malaysia
    Mexico
    Netherlands
    Norway
    Poland
    Portugal
    Romania
    Russian Federation
    Serbia
    Singapore
    Slovakia
    Spain
    Sweden
    Taiwan
    Thailand
    Turkey
    Ukraine
    United Kingdom
    United States
    Vietnam
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months9
    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: 774
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 126
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Elderly patients may require consent from a tutor/legal representative
    I pazienti anziani potrebbero richiedere il consenso di un tutore / rappresentante legale
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 245
    F.4.2.2In the whole clinical trial 900
    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
    Lo sperimentatore o Suo delegato spiegherà ai soggetti quali siano i trattamenti / l'assistenza medica necessari e disponibili secondo le normative locali
    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 Decision2020-04-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-05
    P. End of Trial
    P.End of Trial StatusOngoing
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