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    Summary
    EudraCT Number:2019-002817-21
    Sponsor's Protocol Code Number:AC-065A310
    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 number2019-002817-21
    A.3Full title of the trial
    A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Parallel- Group, Event-Driven, Group-Sequential Study with Open-Label Extension Period to Assess the Efficacy and Safety of Selexipag as Add-On Treatment to Standard of Care in Children Aged =2 to <18 years with Pulmonary Arterial Hypertension.
    Uno studio randomizzato, multicentrico, in doppio cieco, controllato con placebo, a gruppi paralleli, evento-guidato, a gruppi sequenziali con un periodo di estensione in aperto per valutare l’efficacia e la sicurezza di selexipag in aggiunta alla terapia standard in bambini di età compresa tra =2 e <18 anni con ipertensione arteriosa polmonare
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to see if it is safe and helpful to add Selexipag to other PAH medication in children and adolescents.
    uno studio per vedere se è sicuro e di aiuto aggiungere Selexipag agli altri trattamenti per l'ipertensione polmonare arteriosa in bambini ed adolescenti
    A.3.2Name or abbreviated title of the trial where available
    SALTO
    SALTO
    A.4.1Sponsor's protocol code numberAC-065A310
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/123/2019
    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 Uptravi
    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 nameSelexipag
    D.3.2Product code [JNJ-67896049 (ACT-293987)]
    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.3.9.2Current sponsor codeJNJ-67896049 (ACT-293987)
    D.3.9.4EV Substance CodeSUB130805
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 nameSelexipag
    D.3.2Product code [JNJ-67896049 (ACT-293987)]
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeJNJ-67896049 (ACT-293987)
    D.3.9.4EV Substance CodeSUB130805
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    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 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
    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 polmonare arteriosa
    E.1.1.1Medical condition in easily understood language
    Pulmonary Arterial Hypertension (PAH) is a disease of the small pulmonary arteries that is characterized by vascular proliferation and remodeling.
    l'ipertensione polmonare arteriosa è una patologia delle piccole arterie polmonari caratterizzata da proliferazione vascolare e rimodellamento
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    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 whether the addition of selexipag to Standard of Care treatment delays disease progression in children with PAH in comparison to placebo.
    valutare se l'aggiunta di selexipag allo standard of care ritarda il decorso della patologia in pazienti pediatrici con PAH a confronto con placebo
    E.2.2Secondary objectives of the trial
    To assess the safety and tolerability of selexipag in children with PAH.
    To evaluate whether selexipag can delay hospitalization and death due to PAH worsening in children.
    To assess the trough plasma concentrations of selexipag and its active metabolite at steady-state in children with PAH.
    To explore the following safety and efficacy variables.
    To explore the Quality of Life (QoL).
    To explore the long-term safety, tolerability and efficacy of selexipag in children with PAH.
    Valutare la sicurezza e la tollerabilità di selexipag nei bambini con PAH.
    valutare se selexipag può ritardare il ricovero in ospedale e il decesso dovuto a peggioramento della PAH nei bambini.
    valutare le concentrazioni plasmatiche minime di selexipag e dei suoi metaboliti attivi allo stato stazionario nei bambini con PAH.
    esplorare le variabili di sicurezza ed efficacia.
    esplorare la qualità della vita (QoL).
    esplorare la sicurezza, la tollerabilità e l'efficacia a lungo termine di selexipag in bambini con PAH.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Parent(s) (preferably both, if available, or as per local requirements, or their legally authorized representatives [LARs]) must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to allow the child to participate in the study. Assent is also required of children capable of understanding the nature of the study (typically 7 years of age and older) as described in Informed Consent Process in Section 10.4, Regulatory, Ethical, and Study Oversight Considerations.
    2. Male and female participants between =2 and <18 years of age weighing =9 kg at Randomization.
    3. PAH diagnosis confirmed by documented historical RHC performed at any time before participant's screening, and characterized by:
    • mPAP =25 mmHg,
    AND
    • Pulmonary arterial wedge pressure (PAWP) =15 mmHg (in the absence of pulmonary vein obstruction and/or significant lung disease, PAWP can be replaced by left atrial pressure or, in absence of mitral
    stenosis, by left ventricular end diastolic pressure)
    AND
    • Indexed PVR index (PVRi) >3 Wood units × m2.
    4. PAH (WHO Group 1), including patients with Down syndrome, of the following etiologies:
    • Idiopathic PAH (IPAH).
    • Heritable PAH (HPAH).
    • PAH associated with congenital heart disease (PAH-aCHD):
    – PAH with coincidental CHD (ie, a small atrial septal defect, ventricular septal defect, or patent ductus arteriosus that does not itself account for the development of elevated PVR) and if approved by the BCAC, see Section 10.4).
    – Post-operative PAH (persisting / recurring/ developing =6 months after repair of CHD).
    • Drug or toxin-induced.
    • PAH associated with HIV.
    5. WHO FC II and III.
    6. Participants treated with at least 1 PAH-specific treatment, eg, an ERA and/or a PDE-5 inhibitor/soluble guanylate cyclase stimulator, provided that the treatment dose(s) has been stable for at least 3 months prior to screening.
    7. A female participant of childbearing potential (for a definition refer to section 10.6) is eligible only if the following apply:
    Has a negative highly sensitive serum pregnancy test (ß-human chorionic gonadotropin) at screening and a negative urine pregnancy test at randomization.
    Agrees to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation.
    If sexually active, practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies until 30 days after
    last dose of study intervention. It is the responsibility of the investigator to ensure appropriate counselling, including consultation with a specialist (if needed), to the subject and/or parent(s) / LAR(s).
    1. I genitori (preferibilmente entrambi, se disponibili, o secondo i requisiti locali, o i loro rappresentanti legalmente autorizzati) devono firmare il consenso indicante che comprendono lo scopo e le procedure necessarie per lo studio e sono disposti ad acconsentire ala partecipazione dell bambino allo studio. È richiesto anche il consenso dei bambini in grado di comprendere la natura dello studio (in genere di età pari o superiore a 7 anni), come descritto nella sezione 10.4, " Regulatory, Ethical, and Study Oversight Considerations"
    2. Partecipanti maschi e femmine di età compresa tra =2 e <18 anni di peso =9 kg alla randomizzazione.
    3. Diagnosi PAH confermata da RHC storico documentato eseguita in qualsiasi momento prima dello screening del partecipante e caratterizzata da:
    • mPAP =25 mmHg,
    E
    • Pressione del cuneo arterioso polmonare (PAWP) =15 mmHg (in assenza di ostruzione della vena polmonare e / o malattia polmonare significativa, la PAWP può essere sostituita dalla pressione atriale sinistra o, in assenza di stenosi mitrale stenosi, dalla pressione diastolica dell'estremità ventricolare sinistra)
    E
    • Indice PVR indicizzato (PVRi)> 3 unità di legno × m2.
    4. PAH (gruppo 1 dell'OMS), compresi i pazienti con sindrome di Down, delle seguenti eziologie:
    • PAH idiopatico (IPAH).
    • PAH ereditabile (HPAH).
    • PAH associato a cardiopatia congenita (PAH-aCHD):
    - PAH con malattia coronarica coincidentale (cioè un piccolo difetto del setto atriale, difetto del setto ventricolare o dotto arterioso pervio che non tiene conto dello sviluppo di PVR elevato) e se approvato dal BCAC, vedere la Sezione 10.4).
    - PAH post-operatorio (persistente / ricorrente / in sviluppo =6 mesi dopo la riparazione della malattia coronarica).
    • indotto da farmaco o da tossine.
    • PAH associato all'HIV.
    5. OMS FC II e III.
    6. Partecipanti trattati con almeno 1 trattamento specifico per la PAH, ad esempio un ERA e / o un inibitore della PDE-5 / stimolatore della guanilato ciclasi solubile, a condizione che la dose o le dosi di trattamento siano rimaste stabili per almeno 3 mesi prima dello screening .
    7. Una donna in età fertile (per una definizione fare riferimento alla sezione 10.6) è ammissibile solo se si applica quanto segue:
    Ha un test di gravidanza sierico altamente sensibile negativo (gonadotropina corionica ß-umana) allo screening e un test di gravidanza sulle urine negativo alla randomizzazione.
    Accetta di sottoporsi a test di gravidanza sulle urine mensili durante lo studio e fino ad almeno 30 giorni dopo l'interruzione del trattamento in studio.
    Se sessualmente attiva, pratica un metodo altamente efficace di controllo delle nascite coerente con le normative locali relative all'uso di metodi di controllo delle nascite per soggetti che partecipano a studi clinici fino a 30 giorni dopo ultima dose di intervento in studio. È responsabilità dello sperimentatore garantire un'adeguata consulenza, compresa la consultazione con uno specialista (se necessario), al soggetto e / o genitore / i / LAR.
    E.4Principal exclusion criteria
    Etiology
    1. PAH due to portal hypertension, schistosomiasis, pulmonary venoocclusive disease, and/or pulmonary capillary hemangiomatosis.
    2. PAH associated with Eisenmenger syndrome.
    3. Moderate to large left-to-right shuntsa.
    4. Cyanotic congenital cardiac lesions such as transposition of the great arteries, truncus arteriosus, univentricular heart, or pulmonary atresia with ventricular septal defect, as well as subjects with Fontan-palliation.
    5. Participants with PH due to lung disease and/or hypoxia. For participants with Down syndrome, exclusion of lung disease and hypoxia causing PH must be documented (eg, normal oxygen saturation in
    absence of history of lung disease, computed tomography scan, polysomnography, lung function tests). Treatment and intervention
    6. Previous exposure to Uptravi® (selexipag).
    7. Treatment with prostacyclin (epoprostenol) or prostacyclin analogsa (ie, treprostinil, iloprost, beraprost) within 2 months prior to randomization or scheduled to receive any of these treatments during the study.
    8. Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before the planned first dose of study intervention or is currently enrolled in an investigational study
    9. Treatment with strong and moderate inhibitors of CYP2C8 (eg, gemfibrozil, clopidogrel, deferasirox, teriflunomide) from 2 weeks prior to randomization until the last dose of study intervention +3 days
    10. Treatment with inhibitors of UGT1A3 and UGT2B7 (valproic acid, probenecid, and fluconazole) from 2 weeks prior to randomization until the last dose of study intervention + 3 days
    11. Any PAH-related surgical interention planned, or subjects listed for organ transplantation related to PAH.

    Medical history and co-morbidities
    12. Known concomitant life-threatening disease with a life expectancy <12 months
    13. History or current suspicion of intussusception or ileus or gastrointestinal obstruction, per the investigator's judgment
    14. Uncontrolled thyroid disease, per the investigator's judgment
    15. Hemoglobin or hematocrit <75% of the lower limit of normal range
    16. Known severe or moderate hepatic impairment, ie, Child-Pugh Class B or C
    17. Clinical signs of hypotension that, in the investigator's judgment, would preclude initiation of a PAH-specific therapy
    18. Severe renal insufficiency (estimated creatinine clearance <30 mL/min or serum creatinine >221 µmol/L)
    19 Severe coronary heart disease or unstable angina as assessed by the investigator
    20. Myocardial infarction within the last 6 months prior to enrollment
    21. Decompensated cardiac failure if not under close supervision
    22. Severe arrhythmias as assessed by the investigator
    23. Cerebrovascular events (eg, transient ischemic attack, stroke) within the last 3 months prior to enrollment
    24. Congenital or acquired valvular defects with clinically relevant
    myocardial function disorders not related to PH
    Pregnancy and breastfeeding
    25. Pregnant, planning to become pregnant, or lactating
    Other categories
    26. Known allergies, hypersensitivity, or intolerance to selexipag or its excipients (Selexipag IB)
    27. Any known factor or disease that might interfere with treatment compliance, study conduct, or interpretation of the results, such as drug or alcohol dependence or psychiatric disease
    28. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the child (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
    29. inability to swallow tablets whole in water or in soft foods
    Eziologia
    1. PAH causata di ipertensione portale, schistosomiasi, malattia venoocclusiva polmonare e / o emangiomatosi capillare polmonare.
    2. PAH associata a sindrome di Eisenmenger.
    3. Shunt sx/dx da moderato a grande.
    4. Lesioni cardiache congenite cianotiche come trasposizione delle grandi arterie, truncus arteriosus, cuore univentricolare o atresia polmonare con difetto del setto ventricolare, nonché soggetti con palliazione di Fontan.
    5. Partecipanti con PH a causa di malattie polmonari e / o ipossia. Per i partecipanti con sindrome di Down, deve essere documentata l'esclusione della malattia polmonare e dell'ipossia che causa PH (ad es.
    assenza di anamnesi di patologia polmonare, tomografia computerizzata, polisonnografia, test di funzionalità polmonare). Trattamento e intervento
    6. Precedente esposizione a Uptravi® (selexipag)
    7. Il trattamento con prostaciclina (epoprostenolo) o prostaciclina analogsa (cioè treprostinil, iloprost, Beraprost) entro 2 mesi prima della randomizzazione o programmati per ricevere qualsiasi di questi trattamenti durante lo studio.
    8. Ha ricevuto un intervento sperimentale (compresi i vaccini sperimentali) o ha utilizzato un dispositivo medico sperimentale invasivo entro 4 settimane prima della prima dose prevista dell'intervento di studio o è attualmente iscritto a uno studio di sperimentazione
    9. Il trattamento con inibitori forti e moderati di CYP2C8 (ad esempio, gemfibrozil, clopidogrel, deferasirox, teriflunomide) da 2 settimane prima della randomizzazione fino all'ultima dose di intervento studio +3 giorni
    10. Trattamento con inibitori di UGT1A3 e UGT2B7 (acido valproico, probenecid e fluconazolo) da 2 settimane prima della randomizzazione fino all'ultima dose dell'intervento di studio + 3 giorni
    11. Qualunque intervento chirurgico correlato alla PAH pianificato o soggetti elencati per il trapianto di organi correlato alla PAH

    Storia medica e comorbilità
    12. noti concomitanti malattia con una speranza di vita in pericolo di vita <12 mesi
    13. Storia o sospetto attuale di intussuscezione o ileo o ostruzione gastrointestinale, secondo il giudizio dello sperimentatore
    14. Malattia tiroidea incontrollata, secondo il giudizio dello sperimentatore
    15. emoglobina o ematocrito <75% del limite inferiore del range normale
    16. Compromissione della funzionalità epatica grave o moderata nota, ad esempio classe B o C di Child-Pugh
    17. Segni clinici di ipotensione che, secondo il giudizio dello sperimentatore, impedirebbero l'inizio di una terapia specifica per la PAH
    18. Grave insufficienza renale (clearance stimata della creatinina <30 mL / min o creatinina sierica> 221 µmol / L)
    19 malattia coronarica grave o angina instabile, come valutato dal PI
    20. Infarto miocardico negli ultimi 6 mesi prima dell'arruolamento
    21. Insufficienza cardiaca scompensata se non sotto stretto controllo
    22. Aritmie gravi secondo la valutazione dello sperimentatore
    23. Eventi cerebrovascolari (ad es. Attacco ischemico transitorio, ictus) negli ultimi 3 mesi prima dell'arruolamento
    24. Difetti valvolari congeniti o acquisiti con rilevanza clinica disturbi della funzione miocardica non correlati alla PH

    Gravidanza e allattamento
    25. Incinta, in procinto di rimanere incinta o in allattamento altre categorie
    26. Allergie note, ipersensibilità o intolleranza a selexipag o suoi eccipienti (Selexipag IB)
    27. Qualsiasi fattore noto o malattia che potrebbe interferire con il trattamento conformità, condotta di studio o interpretazione dei risultati, come la droga o dipendenza da alcol o malattia psichiatrica
    28. Qualsiasi condizione per la quale, secondo l'investigatore, la partecipazione non sarebbe nell'interesse superiore del bambino (ad es. compromettere il benessere) o che potrebbe prevenire, limitare o confondere il valutazioni specificate dal protocollo
    29. incapacità di ingoiare le compresse con acqua o con cibi non solidi
    E.5 End points
    E.5.1Primary end point(s)
    Time to disease progression from randomization up to 7 days after study treatment discontinuation.
    Tempo alla progressione della malattia dalla randomizzazione fino a 7 giorni dopo l'interruzione del trattamento in studio.
    E.5.1.1Timepoint(s) of evaluation of this end point
    dalla randomizzazione a 7gg dopo la fine del trattamento
    Randomization up to 7 days after EOT.
    E.5.2Secondary end point(s)
    • Treatment-emergent adverse events and serious adverse events.
    • Adverse events leading to premature discontinuation of study treatment
    • Treatment-emergent change in vital signs and body weight from baseline to all assessed time points
    • Growth: Treatment-emergent change in body weight and height from baseline to all assessed time points
    • Sexual maturation (Tanner stage) from baseline to all assessed time points up to 3 days after study treatment discontinuation
    • Treatment-emergent electrocardiogram abnormalities.
    • Treatment-emergent marked laboratory abnormalities at each time point of assessment.
    • Treatment emergent change from baseline in thyroid stimulating hormone over time.
    • Treatment emergent change in selected laboratory variables from baseline to all assessed time points.
    • Time to first Clinical Event Committee-confirmed hospitalization or death due to pulmonary arterial hypertension occurring from Randomization until 7 days after study treatment discontinuation.
    • Trough plasma concentration at steady-state of Selexipag and its metabolite ACT-333679 collected during the maintenance period.

    Exploratory
    • Time to death (all causes) occurring between Randomization and the Analysis Visit for each Analysis.
    • Time to first Clinical Event Committee-confirmed death due to pulmonary arterial hypertension occurring from randomization until 7 days after study treatment discontinuation.
    • Time to Clinical Event Committee- confirmed disease progression up to the Analysis Visit for each Analysis.
    • World Health Organization functional class III (yes/no) at each time point of assessment up to 7 days after study treatment discontinuation.
    • Change in World Health Organization functional class from baseline/enrollment to each time point of assessment up to 7 days after study treatment discontinuation.
    • Change from baseline to each time point of assessment in exercise capacity up to 7 days after study treatment discontinuation as measured by the 6-minute walk distance in children =6 years of age who are developmentally able to understand and perform the test.
    • Change in physical activity (measured by accelerometry) from baseline to 1 year (48 weeks) after Randomization.
    • Change in Panama functional class from baseline to each time point of assessment up to 7 days after study treatment discontinuation.
    • Percent of baseline in plasma N-terminal pro-brain natriuretic peptide at each time point of assessment up to 7 days after study treatment discontinuation.
    • Change from baseline in echocardiographic variables (imaging and Doppler evaluation) such as right ventricular systolic pressure, tricuspid annular plane systolic excursion, etc, at each time point of assessment up to 7 days after study treatment discontinuation.
    • Time to disease progression from randomization up 7 days after study treatment discontinuation defined as:
    1. All-cause death.
    2. Time to non-planned pulmonary arterial hypertension related hospitalization.
    3. Time to pulmonary arterial hypertension related deterioration identified by at least one of the following parameters:
    i. increase in World Health Organization functional class,
    ii. deterioration in exercise testing (15% decrease from baseline of 6- minute walk distance),
    iii. signs or symptoms of right-sided heart failure.
    • Quality of Life as measured by the PedsQL™ 4.0 Generic Core Scales Short Form.Quality of Life as measured by the disease-specific PedsQL™
    3.0 Cardiac Module using the "heart problems and treatment" component only.
    • Quality of Life as measured by the PedsQL™ Multidimensional Fatigue Scale standard version using the "general fatigue" component only.
    • Palatability of the study intervention at Day 1, Week 12, and End of Treatment, assessed using a 5-point facial hedonic scale.
    • Acceptability of the study intervention at Day 1, Week 12, and End of Treatment, as assessed through a 3-point categorical scale as to whether the child swallowed the medication.
    • Eventi avversi emersi dal trattamento ed eventi avversi gravi.
    • Eventi avversi che portano all'interruzione prematura del trattamento in studio
    • Modifica emergente dal trattamento dei segni vitali e del peso corporeo dal basale a tutti i punti temporali valutati
    • Crescita: variazione emergente dal trattamento del peso corporeo e dell'altezza dal basale a tutti i punti temporali valutati
    • Maturazione sessuale (stadio di Tanner) dal basale a tutti i punti temporali valutati fino a 3 giorni dopo l'interruzione del trattamento in studio
    • Anomalie dell'elettrocardiogramma emergente dal trattamento.
    • Anomalie di laboratorio marcate emergenti dal trattamento in ogni momento della valutazione.
    • Nel corso del tempo, il cambiamento emergente dal trattamento rispetto al basale dell'ormone stimolante la tiroide.
    • Modifica emergente del trattamento in variabili di laboratorio selezionate dal basale a tutti i punti temporali valutati.
    • Tempo al primo ricovero o decesso confermato dal comitato per eventi clinici a causa dell'ipertensione arteriosa polmonare che si verifica dalla randomizzazione fino a 7 giorni dopo l'interruzione del trattamento in studio.
    • valutazione della concentrazione plasmatica allo stato stazionario di Selexipag e del suo metabolita ACT-333679 raccolti durante il periodo di mantenimento.

    Esplorativa
    • Tempo trascorso tra randomizzazione e visita di analisi per ciascuna analisi.
    • Tempo alla prima morte confermata dal comitato degli eventi clinici a causa dell'ipertensione arteriosa polmonare che si verifica dalla randomizzazione fino a 7 giorni dopo l'interruzione del trattamento in studio.
    • Time alla progressione della malattia confermata dal CTC fino alla visita di analisi per ciascuna analisi.
    • Classe funzionale III (sì / no) dell'OMS in ogni timepoint fino a 7 gg dopo l'interruzione del trattamento.
    • Modifica della classe funzionale dell'OMS dal basale / iscrizione a ciascun punto di valutazione fino a 7gg dopo l'interruzione del trattamento
    • Passaggio dalla linea di base a ciascun punto temporale della valutazione della capacità di esercizio fino a 7gg dopo l'interruzione del trattamento misurata dalla distanza di camminata di 6 minuti nei bambini di età =6 anni in grado di comprendere ed eseguire il test in modo evolutivo.
    • Variazione dell'attività fisica dal basale a 1 anno (48 settimane) dopo randomizzazione.
    • Modifica della classe funzionale di Panama dal basale a ciascun punto temporale della valutazione fino a 7 gg dopo l'interruzione del trattamento
    • % del basale nel peptide natriuretico N-terminale plasmatico in ciascun momento della valutazione fino a 7 gg dopo l'interruzione del trattamento
    • Variazione rispetto al basale delle variabili ecocardiografiche in ogni momento della valutazione fino a 7 giorni dopo l'interruzione del trattamento
    • Tempo alla progressione della malattia dalla randomizzazione fino a 7gg dopo l'interruzione del trattamento definita come:
    1. Morte per tutte le cause.
    2. Tempo all'ospedalizzazione non pianificata per ipertensione arteriosa polmonare
    3. Tempo al deterioramento correlato all'ipertensione arteriosa polmonare identificato da almeno uno dei seguenti parametri:
    i. aumento della classe funzionale dell'OMS,
    ii. deterioramento dei test da sforzo (riduzione del 15% rispetto al basale della distanza di camminata di 6 minuti),
    iii. segni o sintomi di insufficienza cardiaca destra.
    • Qualità della vita misurata dalla forma breve delle bilance core generiche PedsQL ™ 4.0. Qualità della vita misurata dalla PedsQL ™ specifica della malattia
    3.0 Modulo cardiaco che utilizza solo il componente "problemi cardiaci e trattamento".
    • Qualità della vita misurata dalla versione standard della scala di fatica multidimensionale PedsQL ™ utilizzando solo il componente "fatica generale".
    • Palatabilità dell'intervento di studio al Giorno 1, Settimana 12 e Fine del trattamento, valutata utilizzando una scala edonica facciale a 5 punti.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Disease progression is defined as the first occurrence of either of the
    following components:
    - Death (all causes)
    - Atrial septostomy or Potts' anastomosis, or registration on lung
    transplant list
    - Hospitalization due to worsening pulmonary arterial hypertensiona
    - Clinical worsening of pulmonary arterial hypertension.
    La progressione della malattia è definita come la prima occorrenza di uno dei due
    seguenti componenti:
    - Morte (tutte le cause)
    - Settostomia atriale o anastomosi di Potts o registrazione sul polmone
    lista dei trapianti
    - Ricovero per peggioramento dell'ipertensione arteriosa polmonare
    - Peggioramento clinico dell'ipertensione arteriosa polmonare
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability
    tollerabilità
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    event driven e gruppo equenziale; estensione in aperto
    Event-Driven and Group-Sequential. Open label extension.
    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 EEA41
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Austria
    Belarus
    Belgium
    Brazil
    Bulgaria
    Canada
    China
    Colombia
    Denmark
    Finland
    France
    Germany
    Hungary
    Israel
    Italy
    Korea, Republic of
    Lithuania
    Malaysia
    Mexico
    Netherlands
    Poland
    Portugal
    Romania
    Russian Federation
    Serbia
    Spain
    Sweden
    Switzerland
    Taiwan
    Thailand
    Turkey
    Ukraine
    United States
    Vietnam
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of study is considered as the last scheduled study assessment shown in the Schedule of Activities for the last participant in the study (LVLS).
    La fine dello studio è considerata come l'ultima valutazione programmata dello studio mostrata nel Programma delle attività per l'ultimo partecipante allo studio (LVLS).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    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 years8
    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 Yes
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 60
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 177
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    pediatric subjects
    minori
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 41
    F.4.2.2In the whole clinical trial 237
    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)
    Safety Follow-up Period: starts on the day after the last dose of study intervention (after either the double-blind or the open-label study intervention) and ends 30 days thereafter with a safety telephone call.
    Participants who do not plan to enter the open-label extension (OLEP) period will have this Safety Follow-up Period 30 days after the Analysis Visit for each Analysis. In the OLEP this call constitutes the end of
    study contact.
    Periodo di follow-up di sicurezza: inizia il giorno successivo all'ultima dose del farmaco di studio (dopo l'intervento di studio in doppio cieco o in aperto) e termina dopo 30 giorni con una telefonata di safety.
    I partecipanti che non prevedono di entrare nel periodo di estensione in aperto (OLEP) avranno questo periodo di follow-up di safety 30 giorni dopo la visita di analisi, per ciascuna analisi. Nella OLEP questa chiamata costituisce il contatto finale dello studio.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-04-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-11
    P. End of Trial
    P.End of Trial StatusOngoing
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