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    Summary
    EudraCT Number:2014-004786-25
    Sponsor's Protocol Code Number:AC-077A301
    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:2021-06-17
    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 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
    Uno studio clinico di fase 3 prospettico, multicentrico, in doppio cieco, randomizzato, controllato attivamente, con triplo dummy, a gruppi paralleli, con gruppi sequenziali e disegno adattivo, per confrontare l’efficacia e la sicurezza di macitentan e tadalafil in monoterapia con la corrispondente combinazione a dose fissa in soggetti con ipertensione arteriosa polmonare (PAH), seguito da un periodo di trattamento in aperto con terapia combinata a dose fissa di macitentan e tadalafil
    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).
    Uno studio clinico per confrontare l'efficacia e la sicurezza di macitentan e monotrapie di tadalafil con la corrispondente combinazione a dose fissa in soggetti con ipertensione arteriosa polmonare (PAH).
    A.3.2Name or abbreviated title of the trial where available
    Nap
    Nap
    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 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 number+31715242166
    B.5.5Fax number+31715242110
    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 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 nameCJNJ-68150420-ZZZ-G001 (ACT- 064992D)
    D.3.2Product code [CJNJ-68150420-ZZZ-G001 (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.3.9.2Current sponsor codeJNJ-67896062- AAA
    D.3.9.3Other descriptive nameD.3.6.2 - dose massima specificare: giornaliera D.3.6.2.1 - valore: 10/40 D.3.6.2.2 - unità: mg D.3.6.2.3 - via di somministrazione (riferita alla dose massima): oral use (current)
    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.3.9.2Current sponsor codeJNJ-10291697-AAA
    D.3.9.3Other descriptive nameD.3.6.2 - dose massima specificare: giornaliera D.3.6.2.1 - valore: 10/40 D.3.6.2.2 - unità: mg D.3.6.2.3 - via di somministrazione (riferita alla dose massima): oral use (current)
    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 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 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.3.1Product nameG04BE08
    D.3.2Product code [G04BE08]
    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.3.9.2Current sponsor codeJNJ-10291697-AAA
    D.3.9.3Other descriptive nameD.3.6.2 - dose massima specificare: giornaliera D.3.6.2.1 - valore: 40 D.3.6.2.2 - unità: mg D.3.6.2.3 - via di somministrazione (riferita alla dose massima): oral use (current)
    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 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 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.3.9.2Current sponsor codeJNJ-67896062- AAA
    D.3.9.3Other descriptive nameD.3.6.2 - dose massima specificare: giornaliera D.3.6.2.1 - valore: 10 D.3.6.2.2 - unità: mg D.3.6.2.3 - via di somministrazione (riferita alla dose massima): oral use (current)
    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.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, hard
    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 an increase in blood pressure in the pulmonary arteries leading to shortness of breath, dizziness, fainting and other symptoms.
    L'Ipertensione arteriosa polmonare è un aumento della pressione sanguigna nelle arterie polmonari che porta a mancanza di respiro, vertigini, svenimenti e altri sintomi.
    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
    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 participants 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 participants with symptomatic WHO Group 1 PAH who are PAHspecific treatment-naïve or are currently being treated with a PDE-5i as monotherapy.
    1. Valutare l’effetto della combinazione a dose fissa (FDC) di macitentan 10 mg e tadalafil 40 mg vs. macitentan 10 mg da solo sulla resistenza vascolare polmonare (PVR) alla fine del trattamento in doppio cieco (EDBT) nei partecipanti con PAH sintomatica del gruppo 1 OMS, che non hanno mai ricevuto un trattamento specifico per PAH o stanno attualmente ricevendo un trattamento con un antagonista del recettore delle endoteline (ERA) in monoterapia.
    2. Valutare l’effetto della FDC di macitentan 10 mg e tadalafil 40 mg vs. tadalafil 40 mg da solo sulla PVR alla EDBT nei partecipanti con PAH sintomatica del gruppo 1 OMS, che non hanno mai ricevuto un trattamento specifico per PAH o stanno attualmente ricevendo un trattamento con un inibitore della fosfodiesterasi 5 (PDE 5i) in 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 in participants' cardiopulmonary and cardiovascular function;
    - WHO FC.
    • To evaluate the safety and tolerability of the M/T FDC in the participants population.
    • Valutare l’effetto della FDC macitentan/tadalafil (M/T) in confronto alle rispettive monoterapie, su:
    - capacità di compiere esercizi;
    - sintomi di PAH nella funzionalità cardiopolmonare e cardiovascolare dei partecipanti
    - classe funzionale (FC) OMS
    • Valutare la sicurezza e la tollerabilità della FDC M/T nella popolazione di soggetti.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed and dated ICF.
    2. Male and female participants = 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.
    XML File Identifier: KzoWPcPYh13U0vhfTje6lSaD+VI=
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    - 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 (based on central reading) 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/toxininduced PAH. (Patients for whom no vasoreactivity test was performed at diagnosis can be eligible if currently treated with PAH therapy for more than 3 months and PAH diagnosis confirmed by hemodynamic evaluation at least 3 months after introduction of their PAH therapy).
    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. Modulo di consenso informato firmato e datato.
    2. Partecipanti di sesso maschile e femminile di età = 18 anni e = 75 anni.
    3. Diagnosi confermata di PAH sintomatica nella FC OMS II o III.
    4. PAH sintomatica appartenente a uno dei seguenti sottogruppi di ipertensione polmonare del gruppo 1 secondo OMS [Simonneau 2013]:
    - Idiopatica
    - Ereditaria
    - Indotta da farmaco o tossina
    - Associata a una delle condizioni seguenti:
    o Patologia del tessuto connettivo
    o Infezione da HIV
    o Ipertensione portale
    o Patologia cardiaca congenita con shunt sistemico - polmonare semplice (difetto del setto atriale, difetto del setto ventricolare, dotto arterioso pervio) con ipertensione polmonare persistente, documentata da cateterismo cardiaco destro = 1 anno dopo la riparazione chirurgica.
    5. Diagnosi di PAH confermata tramite valutazione emodinamica a riposo (basata su una lettura centralizzata) , con valutazione nelle 5 settimane precedenti la randomizzazione:
    - Pressione arteriosa polmonare media ¿ 25 mmHg; E
    - Pressione di incuneamento dell’arteria polmonare o pressione telediastolica ventricolare sinistra = 15 mmHg; E
    - PVR ¿ 3 unità Wood (cioè = 240 din·sec·cm-5)
    6. Test di vasoreattività negativo nella PAH idiopatica, ereditaria o indotta da farmaco/tossina. (i partecipanti per i quali non è stato effettuato il test di vasoreattività alla diagnosi sono eleggibili se attualmente in trattamento con terapia per PAH da almeno 3 mesi e con diagnosi di PAH confermata da valutazione emodinamica almeno 3 mesi dopo l’inizio della terapia per PAH).
    7. Nessuna storia di trattamento specifico per PAH o assunzione di una dose stabile di ERA o PDE-5i in monoterapia per almeno 3 mesi prima della baseline RHC, nell’ambito delle dosi pre-specificate di seguito:
    - Bosentan: 250 mg, dose giornaliera totale
    - Macitentan: 10 mg, dose giornaliera totale.
    - Ambrisentan: 10 mg, dose giornaliera totale.
    - Sildenafil: 60-120 mg, dose giornaliera totale.
    - Tadalafil: 40 mg, dose giornaliera totale.
    - Vardenafil: 10 mg, dose giornaliera totale.
    8. Soggetto in grado di sostenere un test di deambulazione di 6 minuti con una distanza minima di 100 m e una distanza massima di 450 m allo screening.
    9. Una donna potenzialmente fertile è idonea solo se una delle condizioni seguenti risulta applicabile:
    - Test di gravidanza sul siero negativo allo screening e test di gravidanza sulle urine negativo alla randomizzazione.
    - Consenso a sottoporsi a test di gravidanza sulle urine con cadenza mensile durante lo studio e fino ad almeno 30 giorni dopo l’interruzione del trattamento sperimentale.
    - Consenso a seguire lo schema di contraccezione dallo screening fino ad almeno 30 giorni dopo l’interruzione del trattamento sperimentale.
    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, elithromycin, nefazodone, ritonavir, or saquinavir) or a moderate dual CYP3A4/CYP2C9 inhibitor (e.g., fluconazole, amiodarone) or coadministration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors 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; lifethreatening 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.

    For a complete overview of the exclusion criteria, please refer to Protocol section 4.4
    Trattamenti per PAH:
    1. Trattamento con uno stimolatore della guanilato ciclasi solubile, L arginina, qualsiasi forma di prostanoide o agonista del recettore della prostaciclina (incl. somministrazione orale, per inalazione o per infusione) nei 3 mesi precedenti l’inizio del trattamento.
    2. Trattamento con terapia combinata di ERA e PDE-5i nei 3 mesi precedenti l’inizio del trattamento oppure storia di intolleranza alla terapia combinata di ERA e PDE-5i.
    3. Ipersensibilità a uno qualsiasi dei trattamenti sperimentali o a uno qualsiasi degli eccipienti delle relative formulazioni.
    Altre terapie:
    4. Trattamento con un forte induttore del citocromo P450 (CYP) 3A4 (ad es. rifabutina, rifampina, rifampicina, rifapentina, carbamazepina, fenobarbitale, fenitoina o erba di San Giovanni) nel mese precedente l’inizio del trattamento.
    5. Trattamento con un forte inibitore CYP3A4 (ad es.ketoconazolo, itraconazolo, voriconazolo, claritromicina, telitromicina, nefazodone, ritonavir o saquinavir) o un inibitore moderato duale di CYP3A4/CYP2C9 (ad es. fluconazolo, amiodarone) o co-somministrazione di una combinazione di inibitore moderato di CYP3A4 e inibitore moderato di CYP2C9, nel mese-precedente l’inizio del trattamento.
    6. Trattamento con doxazosina.
    7. Trattamento con una qualsiasi forma di nitrato organico, sia regolare, sia intermittente.
    8. Inizio o variazione di dosaggio di un trattamento diuretico nella settimana precedente RHC o l’inizio del trattamento.
    9. Trattamento con un altro farmaco sperimentale nei 3 mesi precedenti l’inizio del trattamento.
    Anamnesi/attuali condizioni mediche:
    10. Indice di massa corporea (BMI) > 40 kg/m2 allo screening.
    11. Presenza nota di tre o più dei seguenti fattori di rischio per insufficienza cardiaca con preservata frazione di eiezione allo screening:
    - BMI > 30 kg/m2
    - Diabete mellito di qualsiasi tipo
    - Ipertensione essenziale (anche se ben controllata)
    - Malattia coronarica, ad es. una delle seguenti:
    o Storia di angina stabile; oppure
    o Stenosi superiore al 50% in un’arteria coronarica; oppure
    o Storia di infarto miocardico; oppure
    o Storia di o bypass dell'arteria coronaria programmato e/o stent coronarico.
    12. Presenza nota di malattia polmonare ostruttiva moderata o grave (volume espiratorio forzato in 1 secondo [FEV1] / capacità vitale forzata [FVC] < 70% e FEV1 < 65% del valore previsto dopo la somministrazione di un broncodilatatore) in qualsiasi momento prima dello screening.
    13. Presenza nota di malattia polmonare restrittiva moderata o grave (capacità polmonare totale o FVC < 60% del valore normale previsto) in qualsiasi momento prima dello screening.
    14. Malattia della valvola mitrale o aortica clinicamente significativa; contrazione pericardica; cardiomiopatia sul lato sinistro, restrittiva o congestizia; aritmia cardiaca potenzialmente letale; disfunzione ventricolare sinistra significativa; oppure ostruzione del deflusso ventricolare sinistro.
    15. Fibrillazione atriale permanente nota.
    16. Malattia tiroidea incontrollata nota o sospetta (ipo o ipertiroidismo).
    17. Patologia veno-occlusiva polmonare nota.

    Per una panoramica completa dei critieri di esclusione si prega di fare riferimento da pagina 8 a pagina 11 della Sinossi
    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.
    • Variazione della PVR espressa come il rapporto delle medie geometriche EDBT rispetto alla baseline.
    E.5.1.1Timepoint(s) of evaluation of this end point
    end of double blind treatment (EDBT) E.5.2
    fine del trattamento in doppio cieco (EDBT) E.5.2
    E.5.2Secondary end point(s)
    • Change from baseline to EDBT in 6-minute walk distance.
    • Change from baseline to Week 16 in PAH-SYMPACT™:
    - Cardiopulmonary symptom domain score
    - Cardiovascular symptom domain score
    • Proportion of participants with absence of worsening in WHO FC from baseline to EDBT.
    • Variazione a EDBT rispetto alla baseline nella distanza percorsa in 6 minuti.
    • Variazione alla settimana 16 rispetto al baseline nel PAHSYMPACT™:
    - Punteggio del dominio del sintomo cardiopolmonare
    - Punteggio del dominio del sintomo cardiovascolare
    • Proporzione di partecipanti con assenza di peggioramentodella WHO FC a EDBT rispetto alla baseline.
    E.5.2.1Timepoint(s) of evaluation of this end point
    end of double blind treatment (EDBT)
    fine del trattamento in doppio cieco (EDBT) E.5.2
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA57
    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
    Australia
    Brazil
    Bulgaria
    Canada
    China
    Czechia
    Germany
    Hungary
    Italy
    Japan
    Malaysia
    Mexico
    Poland
    Russian Federation
    South Africa
    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
    Last Visit Last Subject (LVLS)
    Ultima visita dell'ultimo soggetto (LVLS)
    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 months6
    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: 187
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 63
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 127
    F.4.2.2In the whole clinical trial 250
    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.
    Dopo il completamento dello studio o il ritiro prematuro del sogetto dallo studio, a seconda dei casi, lo sperimentatore spiegherà al soggetti quali trattamenti/cure mediche saranno necessarie e disponibili in base alle 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 Decision2019-08-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-16
    P. End of Trial
    P.End of Trial StatusOngoing
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