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    Summary
    EudraCT Number:2019-004131-24
    Sponsor's Protocol Code Number:67896062CTP3001
    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:2021-06-14
    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 number2019-004131-24
    A.3Full title of the trial
    A prospective, randomized, double-blind, multicenter, placebo-controlled, parallel group, adaptive Phase 3 study with open-label extension to evaluate efficacy and safety of macitentan 75 mg in inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension.
    Macitentan in inoperAble or persistent/reCurrent chronIc ThromboEmbolic Pulmonary Hypertension (MACiTEPH)
    Studio adattivo di Fase III, prospettico, randomizzato, in doppio cieco, multicentrico, controllato verso placebo, a gruppi paralleli, con periodo di estensione in aperto, per la valutazione dell’efficacia e della sicurezza di macitentan 75 mg nel trattamento dell’ipertensione polmonare tromboembolica cronica inoperabile o persistente/recidivante.
    (Macitentan in inoperAble or persistent/reCurrent chronIc ThromboEmbolic Pulmonary Hypertension, MACiTEPH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 study to evaluate whether macitentan 75 mg is an effective and safe treatment for patients with inoperable or persistent chronic thromboembolic pulmonary hypertension.
    Uno studio di fase 3 per valutare se macitentan 75 mg è un trattamento efficace e sicuro per i pazienti con ipertensione polmonare tromboembolica cronica inoperabile o persistente.
    A.3.2Name or abbreviated title of the trial where available
    MACiTEPH
    MACiTEPH
    A.4.1Sponsor's protocol code number67896062CTP3001
    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 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 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 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 codeJNJ-67896062-AAA
    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 codeJNJ-67896062-AAA
    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 COMPRESSE
    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 codeJNJ-67896062-AAA
    D.3.9.4EV Substance CodeSUB89247
    D.3.10 Strength
    D.3.10.1Concentration unit mEq/mg milliequivalent(s)/milligram
    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
    Chronic thromboembolic pulmonary hypertension
    Ipertensione polmonare tromboembolica cronica
    E.1.1.1Medical condition in easily understood language
    CTEPH is a rare type of pulmonary hypertension, a condition in which the pressure in the blood vessels going to the lungs (pulmonary arteries) is igher than normal due to restricted blood flow.
    CTEPH è un raro tipo di ipertensione polmonare, in cui la pressione nei vasi sanguigni che arrivano ai polmoni (arterie polmonari) è più elevata del normale a causa di un flusso sanguigno limitato.
    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 evaluate the effect of macitentan 75 mg versus placebo on exercise capacity at Week 28 in participants with chronic thromboembolic pulmonary hypertension (CTEPH).
    Valutare l’effetto di macitentan 75 mg rispetto al placebo sulla capacità di sforzo alla Settimana 28, nei partecipanti con ipertensione polmonare tromboembolica cronica (CTEPH).
    E.2.2Secondary objectives of the trial
    To evaluate the effect of macitentan 75 mg versus placebo on time to clinical worsening up to EODBT.
    To evaluate the effect of macitentan 75 mg versus placebo on WHO FCat Week 28.
    To evaluate the effect of macitentan 75 mg versus placebo on quality of life at Week 28.
    To evaluate the effect of macitentan 75 mg versus placebo on daily physical activity.
    Valutare l’effetto di macitentan 75 mg rispetto al placebo sul tempo al peggioramento clinico fino alla fine del trattamento in doppio cieco.
    Valutare l’effetto di macitentan 75 mg rispetto al placebo sulla WHO FC alla Settimana 28.
    Valutare l’effetto di macitentan 75 mg rispetto al placebo sulla qualità della vita alla Settimana 28.
    Valutare l’effetto di macitentan 75 mg sull’attività fisica quotidiana.
    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: Hemodynamic sub-study v 3.0 of 22 April 2020

    The objective of this sub study is to evaluate the effect of macitentan 75 mg versus placebo on hemodynamic measures in subjects with inoperable or persisten/recurrent CTPEH.

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Sottostudio di Emodinamica, v 3.0 del 22 aprile 2020

    L'obiettivo di questo sottostudio è valutare l'effetto di macitentan 75 mg sulle misurazioni emodinamiche rispetto a placebo, nei soggetti con CTEPH non operabile o persistente/ ricorrente
    E.3Principal inclusion criteria
    • Male or female >= 18 (or the legal age of consent in the jurisdiction in which the study is taking place ) and <=80 years of age.
    • CTEPH (WHO Group 4) fulfilling one of the following criteria:
    a. Inoperable due to the localization of the obstruction being surgically inaccessible (ie, distal disease) as confirmed by the adjudication committee (AC), and diagnosed based on
    • At least 2 of the following assessments in the 14 month-period prior to Randomization: Ventilation / Perfusion (V/Q) scan, pulmonary angiography (PA), computed tomography pulmonary angiogram (CTPA),
    magnetic resonance angiography (MRA).
    - RHC at least 12 weeks after full anticoagulation showing the following (at Screening or in the 24 week period prior to Randomization): mPAP > 20 mmHg, PAWP <=15 mmHg and PVR >=240 dyn·sec/cm5.
    b. Persistent/recurrent CTEPH after BPA, and deemed inoperable due to the localization of the obstruction being surgically inaccessible (ie, distal disease) as confirmed by the AC, diagnosed based on:
    • At least one of the following assessments performed after the latest BPA in the 14-month period prior to Randomization: V/Q scan, PA, CTPA or MRA
    • RHC at least 12 weeks after BPA and full anticoagulation showing the following (at Screening or in the 24-week period prior to Randomization): mPAP > 20 mmHg, PAWP <=15 mmHg and PVR>=240 dyn·sec/cm5.
    c. Persistent/recurrent CTEPH after PEA (including PEA followed by BPA), diagnosed based on:
    • At least one of the following assessments performed after the PEA (and latest BPA following PEA, if applicable) in the 14-month period prior to Randomization: V/Q scan, PA, CTPA or MRA.
    • RHC performed at least 12 weeks after PEA (or latest BPA, if applicable) and full anticoagulationa showing the following (at Screening or in the 24 week period prior to Randomization): mPAP > 20 mmHg,
    PAWP <=15 mmHg and PVR>=240 dyn·sec/cm5.
    • 6MWD = 100 m AND = 450 m, documented by an eligibility and a baseline 6MWT. The baseline 6MWD must not differ by more than 15% from the eligibility test.
    • WHO FC >= I I
    • Participants are to receive riociguat as per local standard of care, unless it is contraindicated or unavailable
    Sottoscrizione di un ICF indicante che i soggetti hanno compreso lo scopo dello studio e le relative procedure e che intendono prendervi parte;
    Uomo o donna di età >=18 (o l'età legale per dare il consenso nel Paese in cui si svolge lo studio) e <=80 anni;
    Presenza di CTEPH (gruppo 4 OMS) che soddisfa i seguenti criteri:
    a. Inoperabilità a causa della posizione dell’ostruzione, che la rende inaccessibile a procedure chirurgiche (ossia malattia distale) con conferma da parte del Comitato di valutazione (adjudication committee, AC) e diagnosi
    basata su •Almeno 2 delle seguenti valutazioni durante i 14 mesi precedenti la Randomizzazione: Scintigrafia ventilatoria e perfusionale (V/Q), angiografia polmonare (pulmonary angiography,( PA), angiografia polmonare con tomografia computerizzata (computed tomography pulmonary angiogram, CTPA), angiografia con risonanza magnetica (MRA).
    •CCdx eseguito almeno 12 settimane in seguito ad anticoagulazione completaa e che rilevi (allo Screening o durante le 12 settimane precedenti la Randomizzazione):
    o mPAP (pressione arteriosa polmonare media, Mean pulmonary artery pressure) >20 mmHg
    o Pressione di incuneamento dell’arteria polmonare (pulmonary artery wedge pressure, PAWP) < =15 mm Hg oppure, se non disponibile o non affidabile, pressione telediastolica ventricolare sinistra (left ventricular end diastolic pressure, LVEDP)< =15 mmHg
    o Resistenza polmonare vascolare (pulmonary vascular resistance, PVR) a riposo >=240 dyn sec/cm5
    b. CTPEH persistente/recidivante in seguito a BPA e ritenuta inoperabile a causa della posizione dell’ostruzione inaccessibile con procedura chirurgica (ossia malattia distale), con conferma da parte dell’AC e diagnosi basata su:
    •Almeno una delle seguenti valutazioni eseguite in seguito all’ultima BPA durante i 14 mesi precedenti la Randomizzazione: Scintigrafia V/Q, PA, CTPA o MRA
    •CCdx almeno 12 settimane in seguito a BPA e anticoagulazione completaa e che rilevi (allo Screening o nelle 12 settimane precedenti la Randomizzazione):
    mPAP > 20 mmHg
    PAWP <=15 mmHg oppure, se non disponibile o non affidabile, LVEDP <=15 mmHg
    PVR >=240 dynsec/cm5
    c. CTPEH persistente/recidivante in seguito ad EAP (compresa EAP seguita da BPA), con diagnosi basata su:
    • Almeno una delle seguenti valutazioni eseguite in seguito all’EAP (e all’ultima BPA successiva all’EAP, ove applicabile) nei 14 mesi precedenti la Randomizzazione: Scintigrafia V/Q, PA, CTPA o MRA
    • CCdx eseguito almeno 24 settimane in seguito a intervento chirurgico (o 12 settimane in seguito a BPA, ove applicabile) e 12 settimane in seguito ad anticoagulazione completa a e che rilevi (allo Screening o nelle 12 settimane precedenti la Randomizzazione):
    mPAP > 20 mmHg
    PAWP <=15 mmHg oppure, se non disponibile o non affidabile, LVEDP <=15 mmHg
    PVR >=240 dyn sec/cm5
    6MWD >= 100 m E <= 450 m, documentata con test 6MWT di idoneità e al basale La 6MWD al basale non deve presentare una differenza superiore al 15% rispetto al test di idoneità
    FC OMS =II
    I partecipanti riceveranno riociguat secondo la locale pratica clinica standard, a meno che non sia controindicato o non disponibile
    Per l'elenco completo dei criteri di inclusione si prega di fare riferimento al Protocollo di studio.
    E.4Principal exclusion criteria
    • Acute pulmonary embolism within 6 months prior to or during Screening.
    • Planned BPA during the fixed duration part of the double blind period. .
    • Significant obstructive and restrictive lung disease.
    • Acute or chronic conditions (other than dyspnea) that limit the ability to comply with study requirements, in particular with 6MWT (eg,
    intermittent claudication).
    • Symptomatic coronary artery disease requiring an intervention within 3 months prior to or during Screening or anticipated during the fixed duration part of the study.
    • Decompensated cardiac failure if not under close supervision.
    • Known and documented life-threatening cardiac arrhythmias.
    • Acute myocardial infarction within 6 months prior to, or during Screening.
    • Cerebrovascular events (including transient ischemic attack) within 3 months prior to, or during Screening.
    • Known or suspicion of pulmonary veno-occlusive disease (PVOD).
    • Administration of ERAs, intravenous prostacyclins / prostacyclin analogs, or investigational treatment within 90 days prior to Randomization.
    • Administration of riociguat within 90 days prior to Randomization (if its use as background medication becomes permissible based on pharmacokinetic DDI data during the conduct of the study, this exclusion
    criterion will no longer apply).
    • Change in dose or initiation of PDE-5 inhibitors, oral inhaled or SC prostacyclins /prostacyclin analogues, prostacyclin receptor agonists (or riociguat, if its use becomes permissible during the study) within 90 days prior to Randomization, or anticipated during the fixed duration part of the DB period.
    • Hypotension, ie, systolic blood pressure (SBP) <90 mmHg or diastolic blood pressure (DBP) <50 mmHg at Screening.
    • Severe renal dysfunction with an estimated Glomerular Filtration Rate <30 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration formula at Screening.
    • Known moderate to severe hepatic impairment, defined as Child-Pugh Class B or C, based on records that confirm documented medical history.
    • Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =1.5 the upper limit of normal (ULN) at Screening.
    • Hemoglobin 100 g/L (<10 g/dL) at Screening.

    Treatment with a strong CYP3A4 inhibitor (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) or a moderate dual CYP3A4/CYP2C9 inhibitor) or co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors within 30 days prior to Randomization.
    1. Embolia polmonare acuta nei 6 mesi precedenti lo Screening o durante lo Screening.
    2. BPA programmata durante la parte a durata fissa del periodo in doppio cieco.
    3. Malattia polmonare significativa ostruttiva o restrittiva che soddisfi uno dei seguenti criteri:
    a. Volume espiratorio massimo in 1 secondo/capacità vitale forzata (VEMS/CVF) <0,7, associato a VEMS <60% rispetto al valore previsto in seguito a somministrazione di broncodilatatore nei partecipanti con anamnesi nota o sospetta di malattia polmonare significativa.
    b. Malattia polmonare restrittiva nota, moderata o grave, ad es. capacità polmonare totale o CVF < 60% rispetto al valore previsto.
    c. Sospetto clinico di fibrosi interstiziale o alveolite diffuse, salvo esclusione delle stesse tramite tomografia computerizzata ad alta risoluzione.
    4. Condizioni acute o croniche (diverse da dispnea) che limitino la capacità di soddisfare i requisiti dello studio, in particolare il 6MWT (ad es. claudicatio intermittens).
    5. Malattia coronarica sintomatica che richieda un intervento (es. intervento coronarico percutaneo, innesto di bypass coronarico) nei 3 mesi precedenti lo Screening o durante lo Screening stesso oppure un intervento anticipato durante la parte a durata fissa dello studio.
    6. Insufficienza cardiaca con scompenso, se non sotto stretta supervisione.
    7. Aritmie cardiache note e documentate potenzialmente letali
    8. Infarto miocardico acuto nei 6 mesi precedenti lo Screening o durante lo Screening.

    Trattamento con forti inibitori di CYP3A4 (ad es. ketoconazolo, itraconazolo, voriconazolo, claritromicina, telitromicina, nefazodone, ritonavir o saquinavir) o inibitori moderati doppi di CYP3A4/CYP2C9 (ad es. fluconazolo, amiodarone) o co-somministrazione di una combinazione di inibitore moderato di CYP3A4 (ad es. ciprofloxacina, ciclosporina, diltiazem, eritromicina, verapamil) e inibitore moderato di CYP2C9 (ad es. miconazolo, piperina) entro 30 giorni prima della randomizzazione.

    Per l'elenco completo dei criteri di esclusione si prega di fare riferimento alla sezione 5.2 del protocollo di studio.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline to Week 28 in exercise capacity (6-minute walk distance [6MWD], as measured by the 6-minute walk test [6MWT]).
    Variazione dal basale alla Settimana 28 della capacità di sforzo (distanza percorsa in 6 minuti [6-minute walk distance, 6MWD] secondo la rilevazione tramite test del cammino dei 6 minuti [6- minute walk test, 6MWT]).
    E.5.1.1Timepoint(s) of evaluation of this end point
    From baseline to Week 28.
    Dal basale alla settimana 28.
    E.5.2Secondary end point(s)
    •Time to first Clinical event committee (CEC) confirmed clinical worsening up to EODBT.
    • Improvement in WHO FC from baseline to Week 28.
    • Change from baseline to Week 28 in:

    • Pulmonary Arterial Hypertension - Symptoms and Impact (PAHSYMPACT®)
    - Cardiopulmonary symptom domain score
    - Cardiovascular symptom domain score

    • Euro Quality of life-5-Dimension-5-Level (EQ-5D-5L©) utility score.
    • Change from baseline to Week 28 in accelerometer-assessed proportion of time spent in moderate to vigorous physical activity.
    Tempo di peggioramento clinico confermato dal Clinical Event Committee (CEC) fino al fine del periodo di trattamento in doppio cieco. Il peggioramento clinico si intende come manifestazione di almeno uno dei seguenti eventi:
    Decesso per qualsiasi causa
    Trapianto cardiaco e/o polmonare
    Ricovero ospedaliero non programmato
    correlato all’ipertensione polmonare (IP) Persistentea aumento della classe funzionale della World Health Organization (WHO FC), non motivato da altre cause (es. infezione virale)
    Persistenta deterioramento pari ad almeno il 15% della capacità di sforzo, rilevata mediante 6MWD
    Nuovi segni o sintomi di insufficienza cardiaca destra, o peggioramento dei segni o sintomi esistenti
    Inizio di terapia specifica per l’IP o incremento del dosaggio di tale terapia a causa di un peggioramento dell’IP rilevato con valutazioni aggiuntive eseguite a discrezione dello sperimentatore e confermato dal CEC.
    Procedure di salvataggio quali endoarteriectomia polmonare (Pulmonary EndArterectomy, PEA) e/o angioplastica polmonare con palloncino (Balloon Pulmonary Angioplasty, BPA) a causa di un peggioramento dell’IP.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 28 and up to End -of-double-blind-treatment (EODBT).
    Settimana 28 e fino al fine del periodo di trattamento in doppio cieco.
    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 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA 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
    Bulgaria
    Canada
    China
    Colombia
    Czechia
    France
    Germany
    Hungary
    Israel
    Italy
    Japan
    Korea, Republic of
    Lithuania
    Mexico
    Poland
    Romania
    Russian Federation
    Saudi Arabia
    Serbia
    Singapore
    Slovakia
    Spain
    Taiwan
    Turkey
    Ukraine
    United Kingdom
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 150
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 95
    F.4.2.2In the whole clinical trial 230
    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/ assistenza medica necessari e disponibili secondo le normative vigenti.
    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 Decision2020-06-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-01
    P. End of Trial
    P.End of Trial StatusOngoing
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