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    Summary
    EudraCT Number:2018-001189-40
    Sponsor's Protocol Code Number:APD811-303
    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:2019-11-14
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-001189-40
    A.3Full title of the trial
    A StuDy EVAluatiNg the Long-Term EffiCacy and Safety of RalinEpag in Subjects with PAH via an Open-Label EXTENSION
    Studio di valutazione dell’efficacia e della sicurezza a lungo termine di ralinepag in soggetti con IAP tramite un’ESTENSIONE in aperto
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An open-label extension (OLE) study to evaluate the long-term safety and efficacy of ralinepag in patients with pulmonary arterial hypertension
    Uno studio di estensione in aperto (OLE) per valutare la sicurezza ed efficacia a lungo termine di ralinepag, in pazienti con ipertensione arteriosa polmonare
    A.3.2Name or abbreviated title of the trial where available
    ADVANCE-extension
    ADVANCE-extension
    A.4.1Sponsor's protocol code numberAPD811-303
    A.5.4Other Identifiers
    Name:IND NumberNumber:109021
    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 SponsorUnited Therapeutics Corporation
    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 supportUnited Therapeutics Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUnited Therapeutics Corporation
    B.5.2Functional name of contact pointRegulatory Department
    B.5.3 Address:
    B.5.3.1Street Address55 T.W. Alexander Drive, PO Box 14186
    B.5.3.2Town/ cityResearch Triangle Park
    B.5.3.3Post codeNC 27709
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1919485-8350
    B.5.5Fax number+1919485-8352
    B.5.6E-mailinfo1@unither.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/3/18/2130
    D.3 Description of the IMP
    D.3.1Product nameRalinepag
    D.3.2Product code APD811
    D.3.4Pharmaceutical form Prolonged-release 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 INNralinepag
    D.3.9.1CAS number 1187856-49-0
    D.3.9.2Current sponsor codeAPD811
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2130
    D.3 Description of the IMP
    D.3.1Product nameRalinepag
    D.3.2Product code APD811
    D.3.4Pharmaceutical form Prolonged-release 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 INNralinepag
    D.3.9.1CAS number 1187856-49-0
    D.3.9.2Current sponsor codeAPD811
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2130
    D.3 Description of the IMP
    D.3.1Product nameRalinepag
    D.3.2Product code APD811
    D.3.4Pharmaceutical form Prolonged-release 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 INNralinepag
    D.3.9.1CAS number 1187856-49-0
    D.3.9.2Current sponsor codeAPD811
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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 (PAH)
    ipertensione arteriosa polmonare (IAP)
    E.1.1.1Medical condition in easily understood language
    high lung blood pressure
    pressione sanguigna polmonare alta
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10077731
    E.1.2Term Pulmonary hypertension WHO functional class I
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is:
    To evaluate the long-term safety and tolerability of ralinepag in subjects who participated in a Phase 2 or Phase 3 study of ralinepag.
    Valutare la sicurezza e la tollerabilità a lungo termine di ralinepag in soggetti che hanno partecipato a uno studio su ralinepag di fase 2 o di fase 3.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are to evaluate the long-term effects of ralinepag on the following parameters:
    • N-terminal pro b-type natriuretic peptide (NT-proBNP)
    • 6-minute walk distance (6MWD)
    • Heart rate recovery (HRR) following completion of the 6-minute walk test (6MWT)
    • WHO/ New York Heart Association (NYHA) functional class
    • Health-related quality of life (HRQoL) measures
    • Proportion of subjects who achieve all three of the following:
    o NT-proBNP <300 pg/mL
    o 6MWD >440 meters
    o WHO/NYHA functional class II status or better
    • Time to all-cause hospitalization
    • Time to all-cause mortality
    • Time to protocol-defined clinical failure events
    Gli obiettivi secondari dello studio sono valutare gli effetti a lungo termine di ralinepag sui seguenti parametri:
    -Frammento N-terminale del propeptide natriuretico di tipo B (NT-proBNP)
    -Distanza percorsa in 6 minuti (6MWD)
    -Recupero del battito cardiaco (HRR) una volta completato il test della distanza percorsa in 6 minuti (6MWD)
    -Classe funzionale dell’OMS/della New York Heart Association (NYHA)
    -Misure della qualità della vita correlata alla salute (HRQoL)
    -Proporzione di soggetti che raggiungono tutti e tre i seguenti parametri:
    NT-proBNP <300 pg/ml
    6MWD >440 metri
    Stato di classe funzionale II, o superiore, secondo l’OMS/la NYHA
    -Tempo al ricovero per qualsiasi causa
    -Tempo al decesso per qualsiasi causa
    -Tempo agli eventi di fallimento clinico definito dal protocollo
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    A pharmacokinetic (PK) substudy is planned at selected sites. Approximately 20 subjects who consented to participate, have completed the Dose Titration Period of the study (if applicable), and have received a stable dose of ralinepag for at least 7 days will participate in the PK Substudy. Collected plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation purposes, stability assessments, metabolite assessments, or to assess other actions of ralinepag with plasma constituents.
    Presso centri selezionati è previsto un sottostudio di farmacocinetica (PK). Circa 20 soggetti, che avranno acconsentito alla partecipazione, avranno completato il periodo di titolazione della dose dello studio (se applicabile) e avranno ricevuto una dose stabile di ralinepag per almeno 7 giorni, parteciperanno al sottostudio PK. I campioni di plasma raccolti per la PK potranno essere usati anche per l’analisi del profilo delle proteine di legame al farmaco, per scopi di validazione del metodo bioanalitico, valutazioni di stabilità, valutazioni dei metaboliti oppure per valutare altre interazioni di ralinepag con costituenti plasmatici.
    E.3Principal inclusion criteria
    Each subject must meet ALL of the following inclusion criteria to be eligible for enrollment into the study:
    1. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any study-related procedures.
    2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
    3. Completed the protocol-defined EOS procedures and EOS Visit in the original ralinepag study.
    4. Both male and female subjects agree to use a highly effective method of birth control throughout the entire study period from informed consent through the 30 day Follow-up Visit, if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in a conception process (i.e., actively attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) during the study and for 30 days after the last dose of IMP. Highly effective birth control methods include the following:
    • oral, implantable, or injectable contraceptives associated with the inhibition of ovulation (starting ≥60 days before dosing) in combination with a diaphragm with vaginal spermicide, cervical cap with vaginal spermicide, or male condom;
    • standard intrauterine device (IUD; e.g., Copper T 380A IUD), intrauterine system (IUS; e.g., LNg 20 IUS - progesterone IUD), progesterone implant, or tubal sterilization (≥180 days after surgery);
    • post vasectomy and male condom, partner using diaphragm with spermicide, cervical cap with spermicide, estrogen and progesterone oral contraceptives (“the pill”), estrogen and progesterone transdermal patch, vaginal ring, or progesterone injection.
    • Complete sexual abstinence defined as refraining from heterosexual intercourse for the entire period of risk associated with study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not acceptable.
    Women who surgically sterile or are postmenopausal (defined as: 12 consecutive months with no menses without an alternative medical cause) are not considered to be of childbearing potential. If of childbearing potential, female partners of male study participants should agree to utilize medically acceptable methods of contraception for the duration of study participation.
    Ogni soggetto deve soddisfare TUTTI i seguenti criteri di inclusione per risultare idoneo all’arruolamento nello studio:
    1. Evidenza di un documento di consenso informato personalmente firmato e datato con cui il soggetto indica di essere stato informato di tutti gli aspetti pertinenti dello studio prima dell’inizio di qualsiasi procedura correlata allo studio.
    2. Il soggetto è disposto e in grado di attenersi alle visite programmate, al piano di trattamento, agli esami di laboratorio e alle altre procedure dello studio.
    3. Completamento delle procedure EOS definite dal protocollo e della visita EOS nello studio di ralinepag originario.
    I soggetti ambosessi acconsentono a usare un metodo di controllo delle nascite altamente efficace per tutta la durata dell’intero periodo dello studio dal consenso informato fino alla visita di follow-up del Giorno 30, qualora sussista il rischio di concepimento. I soggetti idonei ambosessi devono anche acconsentire a non partecipare a un altro processo di concepimento (ovvero, non devono attivamente tentare di avviare una gravidanza o procreare, devono astenersi dalla donazione di sperma e non sottoporsi a procedure di fecondazione in vitro) durante lo studio e nei 30 giorni successivi all’ultima dose dell’IMP. I metodi di controllo delle nascite altamente efficaci comprendono i seguenti:
    • contraccettivi orali, impiantabili o iniettabili associati all’inibizione dell’ovulazione (a partire da =60 giorni prima della somministrazione) in combinazione con un diaframma con spermicida vaginale, cappuccio cervicale con spermicida vaginale o preservativo maschile;
    • dispositivo intrauterino standard (IUD; ad es., IUD Copper T 380A), sistema intrauterino (IUS; ad es., LNg 20 IUS - IUD a base di progesterone), impianto contenente progesterone o sterilizzazione tubarica (=180 giorni dopo l’intervento chirurgico);
    • post-vasectomia e preservativo maschile, utilizzo da parte della compagna di un diaframma con spermicida, cappuccio cervicale con spermicida, contraccettivi orali a base di estrogeno e progesterone (“pillola anticoncezionale”), cerotto transdermico a base di estrogeno e progesterone, anello vaginale o iniezione di progesterone.
    • Astinenza sessuale completa definita come l’astensione da rapporti eterosessuali per l’intero periodo di rischio associato ai trattamenti dello studio. L’affidabilità dell’astinenza sessuale deve essere valutata in relazione alla durata della sperimentazione clinica e allo stile di vita abituale del soggetto. L’astinenza periodica (metodi del calendario, sintotermico, post-ovulazione) non è accettabile. Le donne chirurgicamente sterili o in post-menopausa (definita come: 12 mesi consecutivi con assenza di ciclo mestruale senza una causa medica alternativa) non sono considerate in età fertile. Qualora siano in età fertile, le compagne di partecipanti allo studio di sesso maschile devono acconsentire a utilizzare metodi contraccettivi accettabili dal punto di vista medico per l’intera durata della partecipazione allo studio.
    E.4Principal exclusion criteria
    Eligible subjects must not meet ANY of the following exclusion criteria to be eligible for enrollment into the study:
    1. Subjects who prematurely discontinued investigational medicinal product (IMP) due to a drug-related AE/SAE or tolerability issue in the original ralinepag study in which they were enrolled, or subjects who did not complete all protocol defined study procedures at an EOS Visit (not Early Termination Visit) in the original ralinepag study.
    2. Subjects who withdrew consent during participation in another ralinepag study.
    3. Female subjects who wish to become pregnant or who have a positive pregnancy test on Day 1 (OLE Entry Visit).
    4. Women who are pregnant, lactating or breast-feeding
    5. Subjects who have undergone lung or heart/lung transplant or the initiation of parenteral (intravenous [i.v.] infusion or subcutaneous injection) therapy with a prostacyclin or oral therapy with another IP receptor agonist (selexipag) during the time since participation in their original ralinepag study.
    6. Male subjects with a corrected QT interval using Fridericia’s formula (QTcF) >450 msec and female subjects with QTcF >470 msec on electrocardiogram (ECG) measured on Day 1 (OLE Entry Visit).
    7. Subjects who had an emergency unblinding procedure in a prior Phase 2 or 3 study or subjects who developed withdrawal criteria in their original study but were not withdrawn.
    8. Known hypersensitivity to ralinepag or any of the excipients.
    9. Any reason that, in the opinion of the investigator or medical monitor, precludes the subject from participating in the study, e.g., non-compliance concerns, any previous or intercurrent medical condition that may increase the risk associated with study participation or that would confound study analysis or impair study participation or cooperation.
    I soggetti idonei non devono soddisfare ALCUNO dei seguenti criteri di esclusione per risultare idonei all’arruolamento nello studio:
    1. Soggetti che hanno interrotto prematuramente il prodotto medicinale sperimentale (IMP) a causa di un EA/SAE correlato al farmaco oppure per problemi di tollerabilità nello studio di ralinepag originario in cui erano arruolati, oppure soggetti che non hanno completato tutte le procedure dello studio definite dal protocollo in occasione di una visita EOS (non alla visita di interruzione anticipata) nello studio di ralinepag originario.
    • 2. Soggetti che hanno revocato il consenso durante la partecipazione a un altro studio di ralinepag.
    • 3. Soggetti di sesso femminile che desiderano avviare una gravidanza o che risultano positivi al test di gravidanza eseguito il Giorno 1 (visita di accesso all’OLE).
    • 4. Donne incinte, con montata lattea in atto o che allattano al seno.
    • 5. Soggetti che si sono sottoposti a trapianto di polmone o cuore/polmone o hanno iniziato una terapia parenterale (infusione endovenosa [e.v.] o iniezione sottocutanea) con una prostaciclina o terapia orale con un altro agonista del recettore dell’IP (selexipag) durante il periodo di tempo trascorso dalla partecipazione allo studio di ralinepag originario.
    • 6. Soggetti di sesso maschile con un intervallo QT corretto usando la formula di Fridericia (QTcF) >450 msec e soggetti di sesso femminile con QTcF >470 msec all’elettrocardiogramma (ECG) misurato il Giorno 1 (Visita di accesso all’OLE).
    • 7. Soggetti che si sono sottoposti a una procedura di rivelazione del cieco di emergenza durante un precedente studio di fase 2 o 3 o soggetti che hanno manifestato criteri compatibili con il ritiro nel corso dello studio originale ma che non erano stati ritirati dallo studio.
    • 8. Ipersensibilità nota a ralinepag o a uno qualsiasi degli eccipienti.
    9. Qualsiasi circostanza che, secondo il parere dello sperimentatore o del monitor medico, impedisca al soggetto di partecipare allo studio, ad es., problemi di mancata conformità, qualsiasi condizione medica pregressa o intercorrente che possa aumentare il rischio associato alla partecipazione allo studio o che creerebbe confusione nell’analisi dello studio oppure che possa compromettere la partecipazione o la collaborazione allo studio.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy will be assessed by an evaluation of NT-proBNP; measurement of 6MWD and HRR after completion of the 6MWT; WHO/NYHA functional class assessments; evaluation of HRQoL measures using the Short Form (36) Health Survey (SF-36) and the PAH-Symptoms and Impact (PAH-SYMPACT®) Questionnaires (where validated); time to all-cause hospitalization; time to all-cause mortality, and time to protocol-defined clinical failure events.
    Efficacy endpoints will include an evaluation of:
    • NT-proBNP
    • 6MWD
    • HRR measurements following assessment of 6MWD
    • WHO/NYHA functional class
    • The proportion of subjects who achieve all 3 the following (at specified time points):
    o NT-proBNP level <300 pg/mL
    o 6MWD >440 meters
    o WHO/NYHA functional class II status or better
    • HRQoL measures (where validated)
    • Time to all-cause hospitalization during the study period
    • Time to all-cause mortality during the study period
    • Time to events of protocol-defined clinical failure during the study period
    L’efficacia sarà determinata mediante una valutazione del NT-proBNP; la misurazione della 6MWD e dell’HRR dopo il completamento del 6MWD; valutazioni della classe funzionale secondo l’OMS/la NYHA; la valutazione delle misure HRQoL usando il questionario breve sulla qualità della vita a 36 voci (SF-36) e i questionari sull’impatto e sui sintomi dell’IAP (PAH-SYMPACT®) (laddove validati); il tempo al ricovero per qualsiasi causa; il tempo al decesso per qualsiasi causa e il tempo agli eventi di fallimento clinico definito dal protocollo.
    Gli endpoint di efficacia includeranno:
    • NT-proBNP
    • 6MWD
    • Misurazioni dell’HRR dopo la valutazione della 6MWD
    • Classe funzionale dell’OMS/della NYHA
    • Misure dell’HRQoL (laddove validate)
    • Proporzione di soggetti che raggiungono uno qualsiasi dei seguenti parametri:
    o NT-proBNP <300 pg/ml
    o 6MWD >440 metri
    o Stato di classe funzionale II, o superiore, secondo l’OMS/la NYHA
    • Tempo al ricovero per qualsiasi causa durante il periodo dello studio
    • Tempo al decesso per qualsiasi causa durante il periodo dello studio
    • Tempo agli eventi di fallimento clinico definito dal protocollo durante il periodo dello studio
    E.5.1.1Timepoint(s) of evaluation of this end point
    Continuous endpoints and changes from baseline will be summarized by visit.
    Gli endpoints continui e i cambiamenti rispetto al basale saranno riepilogati per visita.
    E.5.2Secondary end point(s)
    No
    no
    E.5.2.1Timepoint(s) of evaluation of this end point
    No
    no
    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 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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    di estensione
    extension
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 EEA90
    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 No
    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
    Brazil
    Canada
    Chile
    China
    European Union
    Israel
    Korea, Republic of
    Mexico
    Serbia
    Singapore
    Taiwan
    Turkey
    Ukraine
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days6
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months7
    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: 800
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 335
    F.4.2.2In the whole clinical trial 1000
    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)
    Treatment with ralinepag will continue until the subject prematurely discontinues ralinepag treatment due to an AE/SAE or tolerability issues, marketing approval of ralinepag is granted in the region in which the study is conducted, or the study is discontinued by the Sponsor. Should a subject discontinue ralinepag, further participation in the OLE and receipt of ambrisentan and or tadalafil will not occur.
    Il trattamento con ralinepag continua fino all’interruzione prematura del trattamento da parte del soggetto a causa di AE/SAE o problemi di tollerabilità; l'approvazione alla commercializzazione è concessa nel paese in cui lo studio è stato condotto, o in cui lo studio è stato interrotto dallo sponsor. Se un soggetto interrompe il ralinepag, non si verificherà una ulteriore partecipazione all'OLE e il ricevimento di ambrisentan e / o tadalafil.
    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 Decision2019-02-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-21
    P. End of Trial
    P.End of Trial StatusOngoing
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