Flag of the European Union EU Clinical Trials Register Help

Clinical trials

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


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


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

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

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2021-000199-12
    Sponsor's Protocol Code Number:A011-13
    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:2021-09-09
    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 number2021-000199-12
    A.3Full title of the trial
    A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate Sotatercept When Added to Background Pulmonary Arterial Hypertension (PAH) Therapy in Newly Diagnosed Intermediate- and High-risk PAH Patients.
    Studio di Fase 3, randomizzato, in doppio cieco, controllato con placebo per valutare Sotatercept quando aggiunto alla terapia di base per l’ipertensione arteriosa polmonare (PAH) in pazienti con nuova diagnosi di PAH,ad intermedio ed alto rischio.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 Study of Sotatercept in Newly Diagnosed Intermediate- and
    High-risk Pulmonary arterial hypertension (PAH) Patients.
    Studio di fase 3 su sotatercept in pazienti con ipertensione arteriosa polmonare (IAP) di nuova diagnosi a rischio intermedio ed elevato.
    A.3.2Name or abbreviated title of the trial where available
    A Phase 3 Study of Sotatercept in Newly Diagnosed Intermediate- and High-risk PAH Patients
    Studio di fase 3 su sotatercept in pazienti con IAP di nuova diagnosi a rischio intermedio ed elevat
    A.4.1Sponsor's protocol code numberA011-13
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN00000000
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00000000
    A.5.3WHO Universal Trial Reference Number (UTRN)U0000-0000-0000
    A.5.4Other Identifiers
    Name:INDNumber:136150
    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 SponsorACCELERON PHARMA INC.
    B.1.3.4CountryUnited States
    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 supportAcceleron Pharma Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcceleron Pharma Inc.
    B.5.2Functional name of contact pointSaraBeth Hahn
    B.5.3 Address:
    B.5.3.1Street Address128 Sidney Street
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number0014847675150
    B.5.5Fax number000000
    B.5.6E-mailshahn@acceleronpharma.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/20/2369
    D.3 Description of the IMP
    D.3.1Product nameSotatercept
    D.3.2Product code [ACE-011]
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSOTATERCEPT
    D.3.9.1CAS number 1001080-50-7
    D.3.9.2Current sponsor codeACE-011
    D.3.9.3Other descriptive nameActRIIA-IgG1Fc
    D.3.9.4EV Substance CodeSUB179718
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 placeboLyophilisate for solution for injection
    D.8.4Route of administration of the placeboSubcutaneous 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 (PAH)
    Ipertensione arteriosa polmonare (IAP)
    E.1.1.1Medical condition in easily understood language
    Cardiovascular Disease
    Malattia cardiovascolare
    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
    The objective of this study is to evaluate the effects of sotatercept treatment (plus background PAH therapy) versus placebo (plus background PAH therapy) on TTCW in participants who are newly diagnosed with PAH and are at intermediate or high risk of PAH disease progression.
    L’obiettivo di questo studio è valutare gli effetti del trattamento con sotatercept (in aggiunta alla terapia di base per l’IAP) rispetto al placebo (in aggiunta alla terapia di base per l’IAP) sul tempo al peggioramento clinico (Time To Clinical Worsening, [TTCW]) in partecipanti che ricevono una nuova diagnosi di IAP e sono a rischio intermedio o elevato di progressione della malattia dell’IAP.
    E.2.2Secondary objectives of the trial
    -
    -
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age = 18 years
    2. Documented diagnostic right heart catheterization (RHC) within 6 months of screening documenting a minimum PVR of = 4 Wood units and pulmonary capillary wedge pressure (PCWP) or left ventricular enddiastolic pressure (LVEDP) of = 15 mmHg, with the diagnosis of WHO PAH Group 1 in any of the following subtypes:
    - Idiopathic PAH
    - Heritable PAH
    - Drug/toxin-induced PAH
    - PAH associated with connective tissue disease
    - PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following repair
    3. Symptomatic PAH classified as WHO FC II or III
    4. REVEAL Lite 2 risk score = 6
    5. Diagnosis of PAH within 6 months of screening and on stable doses of a double combination of background PAH therapies for at least 90 days prior to screening. A triple combination of therapies, with stable doses for 90 days, may be allowed per local standard-of-care guidelines, but is restricted to 10% of the study population.
    6. Six-minute walk distance = 150 m repeated twice at screening at least 4 hours apart, but no longer than 1 week apart, and both values are within 15% of each other (calculated from the highest value)
    7. Females of childbearing potential must meet the following criteria:
    -Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study drug administration; she must agreeto ongoing urine or serum pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug -If sexually active, have used, and agree to use, highly effective contraception without interruption, for at least 28 days prior to starting the investigational product, during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study treatment -Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study treatment
    8. Male participants must meet the following criteria:
    -Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy
    -Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study treatment
    9. Ability to adhere to study visit schedule and understand and comply with all protocol requirements
    10. Ability to understand and provide written informed consent
    1. Età =18 anni
    2. Diagnosi documentata di cateterismo cardiaco destro (Right Heart Catheterization, [RHC]) entro 6 mesi dallo screening che documenta una RVP minima di = 4 unità Wood e una pressione di incuneamento dei capillari polmonari (Pulmonary Capillary Wedge Pressure, [PCWP]) o pressione telediastolica ventricolare sinistra (Left Ventricular End-Diastolic Pressure, [LVEDP]) = 15 mmHg, con diagnosi di IAP di Gruppo 1 secondo l’OMS in uno qualsiasi dei seguenti sottotipi:
    - IAP idiopatica
    - IAP ereditaria
    - IAP indotta da farmaco/tossina
    - IAP associata a malattia del tessuto connettivo
    - IAP associata a shunt semplici, congeniti da sistemici a polmonari ad almeno 1 anno dopo la riparazione
    3. IAP sintomatica classificata come classe funzionale (Functional Class, [FC]) II o III dell’OMS
    4. Punteggio di rischio secondo il registro per valutare la gestione precoce e a lungo termine della malattia da IAP (Registry to Evaluate Early and Long Term PAH Disease Management, [REVEAL]) Lite 2 = 6
    5. Diagnosi di IAP nei 6 mesi precedenti lo screening e assunzione di dosi stabili di una doppia combinazione di terapie di base per l’IAP da almeno 90 giorni prima dello screening. Potrebbe essere consentita una tripla combinazione di terapie, con dosi stabili per 90 giorni, in base alle linee guida locali dello standard di cura, seppur limitatamente al 10% della popolazione dello studio
    6. Distanza percorsa a piedi in 6 minuti = 150 m ripetuta due volte allo screening (misurata ad almeno 4 ore di distanza, ma non più di 1 settimana) con entrambi i valori compresi entro il 15% degli stessi (calcolati dal valore più alto)
    7. Le donne in età fertile devono soddisfare i seguenti criteri:
    - Avere 2 risultati negativi al test di gravidanza sulle urine o sul siero verificati dallo sperimentatore prima di iniziare la somministrazione del farmaco in studio; le pazienti dovranno accettare di sottoporsi a test di gravidanza sulle urine o sul siero durante il corso dello studio e fino a 8 settimane dopo l’ultima dose del farmaco in studio - Se sessualmente attive, utilizzato e accettare di utilizzare un metodo contraccettivo altamente efficace senza interruzione per almeno 28 giorni prima di iniziare il prodotto sperimentale, durante lo studio (comprese le interruzioni della dose) e per 16 settimane (112 giorni) dopo l’interruzione del trattamento dello studio - Astenersi dall’allattare al seno un bambino o dal donare sangue od ovuli per tutta la durata dello studio e per almeno 16 settimane (112 giorni) dopo l’ultima dose di trattamento dello studio
    8. I partecipanti di sesso maschile devono soddisfare i seguenti criteri:
    - Acconsentire a utilizzare un preservativo, definito come un preservativo maschile in lattice o un preservativo non in lattice NON composto di membrana naturale (animale) (per es., poliuretano), durante il contatto sessuale con una donna incinta o con una donna in età fertile durante la partecipazione allo studio, durante le interruzioni della dose e per almeno 16 settimane (112 giorni) dopo l’interruzione del prodotto sperimentale, anche se si sono sottoposti a vasectomia eseguita con successo
    - Astenersi dal donare sangue o sperma per tutta la durata dello studio e per 16 settimane (112 giorni) dopo l’ultima dose di trattamento dello studio
    9. Capacità di aderire al programma di visite dello studio e comprendere e rispettare tutti i requisiti previsti dal protocollo
    10. Capacità di comprendere e fornire il consenso informato scritto
    E.4Principal exclusion criteria
    1. Diagnosis of PAH WHO Groups 2, 3, 4, or 5
    2. Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH and PAH associated with portal hypertension
    3. Hemoglobin at screening above gender-specific upper limit of normal (ULN), per local laboratory test
    4. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mmHg or sitting diastolic BP > 100 mmHg during the Screening Visit after a period of rest
    5. Baseline systolic BP < 90 mmHg at screening
    6. Pregnant or breastfeeding women
    7. Any of the following clinical laboratory values at the Screening
    Visit:
    -Estimated glomerular filtration rate < 30 mL/min/m2 (as defined by MDRD equation)
    -Serum alanine aminotransferase or aspartate aminotransferase levels > 3 × ULN or total bilirubin > 1.5 × ULN -Platelet count < 50,000/mm3 (< 50.0 × 109/L)
    8. Currently enrolled in or have completed any other investigational product study within 30 days for small-molecule drugs or within 5 halflives for biologics prior to the date of signed informed consent
    9. Known allergic reaction to sotatercept (ACE-011)
    10. History of pneumonectomy
    11. Pulmonary function test values of forced vital capacity < 60% predicted within 1 year prior to the Screening Visit
    12. Stopped receiving any pulmonary hypertension chronic general supportive therapy (e.g., diuretics, oxygen, anticoagulants, and digoxin) within 60 days prior to the Screening Visit
    13. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to the Screening Visit or planned initiation during the study (participants who are stable in the maintenance phase of a program and who will continue for the duration of the study are eligible)
    14. Untreated obstructive sleep apnea
    15. History of known pericardial constriction
    16. History of restrictive or congestive cardiomyopathy
    17. History of atrial septostomy within 180 days prior to the Screening Visit
    18. Electrocardiogram with Fridericia's corrected QT interval > 450 ms (or > 500 ms if right bundle branch abnormality is present) during the Screening Period
    19. Personal or family history of long QT syndrome or sudden cardiac death
    20. Left ventricular ejection fraction < 50% on historical echocardiogram within 1 year prior to the Screening Visit or pulmonary capillary wedge pressure > 15 mmHg as determined by historical RHC within 6 months prior to the Screening Visit
    21. Any current or prior history of symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) in the past 6 months prior to the Screening Visit
    22. Cerebrovascular accident within 3 months prior to the Screening Visit
    23. Acutely decompensated heart failure within 30 days prior to the Screening Visit, as per investigator assessment
    24. Significant (= 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease
    25. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, and vasopressin) within 30 days prior to the Screening Visit
    1. Diagnosi di IAP dei Gruppi 2, 3, 4 o 5 secondo l’OMS
    2. Diagnosi dei seguenti sottotipi di IAP del Gruppo 1: IAP associata a virus dell’immunodeficienza umana (Human Immunodeficiency Virus, [HIV]) e IAP associata a ipertensione portale
    3. Emoglobina allo screening al di sopra del limite superiore della norma (Upper Limit of Normal, [ULN]) specifico per il sesso, secondo il test di laboratorio locale
    4. Ipertensione sistemica non controllata, come evidenziato dalla pressione arteriosa (PA) sistolica in posizione seduta > 160 mmHg o PA diastolica in posizione seduta > 100 mmHg durante la visita di screening dopo un periodo di riposo
    5. PA sistolica al basale < 90 mmHg allo screening
    6. Stato di gravidanza o allattamento
    7. Uno qualsiasi dei seguenti valori clinici di laboratorio alla visita di screening:
    - Velocità di filtrazione glomerulare stimata < 30 ml/min/m2 (come definito mediante equazione MDRD [Modification of Diet in Renal Disease, modifica della dieta nelle malattie renali])
    - Livelli sierici di alanina aminotransferasi o aspartato aminotransferasi > 3 volte l’ULN o bilirubina totale > 1,5 volte l’ULN - Conta piastrinica < 50.000/mm3 (< 50,0 × 109/l)
    8. Attuale arruolamento in, o completamento di qualsiasi altro studio con prodotto sperimentale entro 30 giorni per i farmaci micromolecolari oppure entro 5 emivite per i farmaci biologici prima della data della firma del consenso informato
    9. Reazione allergica nota a sotatercept (ACE-011)
    10. Anamnesi di pneumonectomia
    11. Valori di capacità vitale forzata nei test di funzionalità polmonare < 60% del valore previsto entro 1 anno prima della visita di screening
    12. Interruzione di qualsiasi terapia di supporto cronica generale per ipertensione polmonare (per es., diuretici, ossigeno, anticoagulanti e digossina) nei 60 giorni precedenti la visita di screening
    13. Avvio di un programma di attività fisica per la riabilitazione cardiopolmonare nei 90 giorni precedenti la visita di screening o inizio programmato durante lo studio (sono idonei i partecipanti che sono stabili nella fase di mantenimento di un programma e che continueranno per tutta la durata dello studio)
    14. Apnea ostruttiva del sonno non trattata
    15. Anamnesi di costrizione pericardica nota
    16. Anamnesi di cardiomiopatia restrittiva o congestizia
    17. Anamnesi di settostomia atriale nei 180 giorni precedenti la visita di screening
    18. Elettrocardiogramma con intervallo QT corretto secondo la formula di Fridericia > 450 ms (o > 500 ms se è presente un’anomalia di branca destra) durante il periodo di screening
    19. Anamnesi personale o familiare di sindrome del QT lungo o decesso cardiaco improvviso
    20. Frazione di eiezione ventricolare sinistra < 50% all’ecocardiogramma anamnestico entro 1 anno prima della visita di screening o pressione di incuneamento dei capillari polmonari > 15 mmHg come stabilito dall’RHC anamnestico nei 6 mesi precedenti la visita di screening
    21. Qualsiasi anamnesi attuale o pregressa di coronaropatia sintomatica (precedente infarto miocardico, intervento coronarico percutaneo, intervento chirurgico per l’innesto di bypass aortocoronarico o dolore toracico da angina cardiaca) nei 6 mesi precedenti la visita di screening
    22. Ictus cerebrovascolare nei 3 mesi precedenti la visita di screening
    23. Insufficienza cardiaca scompensata acuta nei 30 giorni precedenti la visita di screening, secondo la valutazione dello sperimentatore
    24. Malattia valvolare da rigurgito mitralico o rigurgito aortico significativa (rigurgito = 2+)
    25. Inotropi per via endovenosa (per es., dobutamina, dopamina, norepinefrina e vasopressina) ricevuti nei 30 giorni precedenti la visita di screening
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is TTCW, defined as the first confirmed morbidity event or death. The events that will comprise this endpoint include the following:
    • All-cause death
    • Non-planned PAH-related hospitalization of = 24 hours in duration
    • Atrial septostomy
    • Lung transplant
    • Deterioration in performance in exercise testing due to PAH, defined as a decrease in 6MWD from baseline on
    2 consecutive tests (which must be at least 4 hours apart) and at least 1
    of the following:
    - Worsening of WHO FC from baseline
    - Signs/symptoms of increased right heart failure
    - Addition of a background PAH therapy or change in the composition of
    PAH background therapy, including an increase in parenteral prostacyclin of = 10%
    All events will be adjudicated by a blinded, independent committee of clinical experts.
    L’endpoint primario di efficacia è il TTCW, definito come il primo evento di morbilità confermato o decesso. Gli eventi che comprenderanno questo endpoint includono i seguenti:
    • Decesso per qualsiasi causa
    • Ricovero non programmato correlato all’IAP di durata = 24 ore
    • Settostomia atriale
    • Trapianto polmonare
    • Deterioramento delle prestazioni nei test da sforzo a causa dell’IAP, definito come una diminuzione della distanza percorsa a piedi in 6 minuti (Six-Minute Walk Distance, [6MWD]) rispetto al basale in 2 test consecutivi (che devono essere eseguiti ad almeno 4 ore di distanza) e almeno 1 dei seguenti:
    - Peggioramento della FC dell’OMS rispetto al basale
    - Segni/Sintomi di aumento dell’insufficienza cardiaca destra
    - Aggiunta di una terapia di base per l’IAP o variazione nella composizione della terapia di base per l’IAP, incluso un aumento della prostaciclina parenterale = 10%
    Tutti gli eventi saranno validati da un comitato indipendente in cieco di esperti clinici.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint will be analyzed using a weighted stratified logrank test with randomization stratification factors as strata. The Cui-Hung-Wang (CHW) method will be used to control the overall Type I error rate. The point estimate of the hazard ratio with 95% CI will be estimated by a Cox regression model stratified by the randomization factors. If there is no increase in the number of events and sample size following the planned interim analysis, then the CHW method will be the same as a conventional analysis of this data. The Chen-DeMets-Lan method will be used as a supportive analysis to the CHW method.
    L’endpoint primario sarà analizzato utilizzando un test dei ranghi logaritmici stratificato ponderato con fattori di stratificazione della randomizzazione come strati. Per controllare il tasso di errore complessivo di tipo I verrà impiegato il metodo di Cui-Hung-Wang (CHW). La stima puntuale del rapporto di rischio con IC al 95% sarà stimata mediante un modello di regressione di Cox stratificato in base ai fattori di randomizzazione. Se non vi è alcun aumento nel numero di eventi e nella dimensione del campione dopo l’analisi ad interim programmata, il metodo CHW sarà lo stesso di un’analisi convenzionale di questi dati. Il metodo di Chen-DeMets-Lan sarà utilizzato come analisi di supporto al metodo CHW.
    E.5.2Secondary end point(s)
    1. Multicomponent improvement endpoint measured by the proportion of participants achieving all of the following at Week 24 relative to baseline:
    -Improvement in 6MWD (increase = 30 m)
    -Improvement in NT-proBNP (decrease in NT-proBNP = 30%) or maintenance/achievement of NT-proBNP level < 300 ng/L
    -Improvement in WHO FC or maintenance of WHO FC II
    2. Proportion of participants who achieve a low REVEAL Lite 2 risk score at Week 24 versus baseline
    3. Proportion of participants who maintain or achieve a low risk score at Week 24 versus baseline using the simplified French Risk score calculator
    4. Change from baseline in NT-proBNP levels at Week 24
    5. Proportion of participants who improve in WHO FC or maintain WHO FC II at 24 weeks from baseline
    6. Change from baseline in 6MWD at Week 24
    7. Change from baseline in EuroQol - 5 dimensions scale 5 levels (EQ-5D- 5L) index score at Week 24
    8. Change from baseline in Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT)® at Week 24
    1. Endpoint di miglioramento multicomponente misurato mediante la percentuale di partecipanti che raggiunge tutto quanto segue alla Settimana 24 rispetto al basale:
    - Miglioramento della 6MWD (aumento = 30 m)
    - Miglioramento del frammento N-terminale del propeptide natriuretico di tipo B (N-terminal Prohormone B-type Natriuretic Peptide, [NT-proBNP]) (diminuzione di NT-proBNP = 30%) o mantenimento/raggiungimento del livello di NT-proBNP < 300 ng/l
    - Miglioramento della FC dell’OMS o mantenimento della FC II dell’OMS
    2. Percentuale di partecipanti che raggiunge un basso punteggio di rischio REVEAL Lite 2 alla Settimana 24 rispetto al basale
    3. Percentuale di partecipanti che mantiene o raggiunge un punteggio di basso rischio alla Settimana 24 rispetto al basale utilizzando il calcolatore semplificato francese del punteggio di rischio
    4. Variazione rispetto al basale nei livelli di NT-proBNP alla Settimana 24
    5. Percentuale di partecipanti che migliora nella FC dell’OMS o mantiene la FC II dell’OMS a 24 settimane rispetto al basale
    6. Variazione rispetto al basale nella 6MWD alla Settimana 24
    7. Variazione rispetto al basale nel punteggio indice del questionario europeo sulla qualità della vita a 5 dimensioni e 5 livelli (European Quality of life 5-Dimensions 5-Levels, [EQ-5D-5L]) alla Settimana 24
    8. Variazione rispetto al basale nel questionario sull’ipertensione arteriosa polmonare - sintomi e impatto (Pulmonary Arterial Hypertension Symptoms and Impact, [PAH-SYMPACT®]) alla Settimana 24
    E.5.2.1Timepoint(s) of evaluation of this end point
    week 24; Settimana 24
    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 Yes
    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 No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA72
    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
    Belgium
    Brazil
    Canada
    Chile
    Colombia
    Croatia
    Czechia
    France
    Germany
    Greece
    Ireland
    Israel
    Italy
    Korea, Democratic People's Republic of
    Korea, Republic of
    Netherlands
    New Zealand
    Poland
    Portugal
    Serbia
    South Africa
    Spain
    Sweden
    Switzerland
    Taiwan
    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
    The end of the study is defined as when the last participant completes the last visit.
    La fine di questo studio è definita come la data in cui l’ultimo partecipante completa l’ultima visita.
    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: 497
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 165
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 303
    F.4.2.2In the whole clinical trial 662
    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)
    -
    -
    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 Decision2021-11-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-01-26
    P. End of Trial
    P.End of Trial StatusOngoing
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA