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    EudraCT Number:2012-003335-33
    Sponsor's Protocol Code Number:AC-055-305
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-01-11
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2012-003335-33
    A.3Full title of the trial
    A multi-center, double-blind, randomized, placebo-controlled, parallel-group, Phase 3 study to evaluate the effects of macitentan on exercise capacity in subjects with Eisenmenger Syndrome.
    Studio di fase III, multicentrico, in doppio cieco, randomizzato, controllato con placebo, a gruppi paralleli per valutare gli effetti di macitentan sulla capacità di esercizio fisico in soggetti affetti dalla Sindrome di Eisenmenger.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate if macitentan is efficient, safe and tolerable to be used for treatment of Eisenmenger Syndrome.
    Studio per valutare se macitentan è efficace, sicuro e tollerabile per il trattamento della Sindrome di Eisenmenger.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberAC-055-305
    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.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.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationActelion Pharmaceuticals Ltd.
    B.5.2Functional name of contact pointGlobal Medical Information
    B.5.3 Address:
    B.5.3.1Street AddressGewerbestrasse 16
    B.5.3.2Town/ cityAllschwil
    B.5.3.3Post code4123
    B.5.4Telephone number.
    B.5.5Fax number.
    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/3/11/909
    D.3 Description of the IMP
    D.3.1Product nameMacitentan
    D.3.2Product code ACT-064992
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMacitentan
    D.3.9.1CAS number 441798-33-0
    D.3.9.2Current sponsor codeACT-064992
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Eisenmenger Syndrome
    Sindrome di Eisenmenger
    E.1.1.1Medical condition in easily understood language
    Condition caused by a defect in the heart that affects blood flow between the heart and the lungs.
    Condizione causata da un difetto del cuore che interessa il flusso sanguigno tra il cuore e i polmoni.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10058554
    E.1.2Term Eisenmenger's syndrome
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic 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 demonstrate that macitentan improves exercise capacity in
    comparison with placebo in subjects with Eisenmenger Syndrome (ES).
    Dimostrare che macitentan migliora la capacità di esercizio fisico rispetto al placebo in soggetti affetti dalla Sindrome di Eisenmenger (SE).
    E.2.2Secondary objectives of the trial
    To evaluate the effects of macitentan in comparison with placebo on:
    – World Health Organization (WHO) functional class,
    – Dyspnea (assessed by the Borg dyspnea index),
    – Quality of life (QoL; assessed by the Short-Form 36(SF-36)questionnaire).
    Valutare gli effetti di macitentan rispetto al placebo per:
    – Classe funzionale WHO,
    – Dispnea (valutata con la scala di Borg),
    – Qualità della vita (QoL; misurata con il questionario Short-Form 36 (F36)).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    "Hemodynamic sub-study", Version 1.ITA.A, date 23-10-2012

    "Sottostudio di emodinamica", Versione 1.ITA.A, data 23-10-2012

    E.3Principal inclusion criteria
    - Males or females ≥ 18 and ≤ 70 years of age.
    - Subjects with confirmed ES (European Society of Cardiology
    [ESC] and the European Respiratory Society [ERS]
     Established by echocardiography as:
    o Isolated ASD > 2 cm in diameter,
    o or isolated VSD > 1 cm in diameter,
    o or presence of both ASD and VSD (with either VSD
    ≤ 1 cm in diameter and ASD > 2 cm in diameter, or
    VSD > 1 cm in diameter and ASD ≤ 2 cm in diameter,
    or VSD > 1 cm in diameter and ASD > 2 cm in diameter),
    o and right to left shunt or bi-directional shunt with
    prevalent right to left direction.
     Unoperated, or previously palliated surgically for defects
    mentioned above (incomplete closure).
     Resting peripheral arterial oxygen saturation (SaO2)
    ≤ 90% and >70% (pulse oximetry, room air).
    - Cardiac catheterization measurements must show the following:
     Mean resting pulmonary arterial pressure (mPAP)> 25 mmHg,
     Pulmonary capillary wedge pressure (PCWP) or mean left atrial pressure (LAP) or left ventricular end diastolic
    pressure (LVED) ≤ 15 mmHg,
     Pulmonary vascular resistance (PVR) ≥ 800 dyn∙s/cm5 or ≥ 10 Wood units.
    - Subjects with WHO functional class ≥ II.
    - Subjects able to perform the 6-minute walk test (6MWT)with a minimum distance of 50 m and a maximum distance
    of 450 m.
    - Uomini o donne di età ≥ 18 e ≤ 70 anni.
    - Soggetti con Sindrome di Eisenmenger confermata (Linee guida della Società Europea di Cardiologia [ESC] e della Società Europea per le Malattie Respiratorie [ERS]):
    • Accertata da ecocardiografia come:
    o ASD isolato &gt; 2 cm di diametro
    o oppure VSD isolato &gt; 1cm di diametro
    o oppure presenza di entrambi ASD e VSD (con VSD ≤ 1 cm di diametro e ASD &gt; 2 cm di diametro, o VSD &gt; 1 cm di diametro e ASD ≤ 2 cm di diametro, o VSD &gt; 1 cm di diametro e ASD &gt; 2 cm di diametro)
    o e shunt da destra a sinistra o shunt bidirezionale con direzione prevalente da destra a sinistra.
    • Non operato o precedentemente sottoposto a chirurgia palliativa per i difetti suddetti (chiusura incompleta).
    • Saturazione arteriosa periferica dell'ossigeno a riposo (SaO2) ≤ 90% e &gt;70% (pulsossimetria, aria ambiente).
    - Le misurazioni del cateterismo cardiaco devono evidenziarequanto segue:
    • Pressione arteriosa polmonare media a riposo (mPAP) &gt; 25 mmHg
    • Pressione capillare polmonare incuneata (PCWP) o pressione atriale sinistra media (LAP) o pressione diastolica terminale ventricolare sinistra (LVED) ≤ 15 mmHg
    • Resistenza vascolare polmonare (PVR) ≥ 800 dyn∙s/cm5 o ≥ 10 unità Wood.
    - Soggetti con classe funzionale WHO ≥ II.
    - Soggetti capaci di eseguire il test della camminata in 6 minuti (6MWT) con una distanza minima di 50 m e una distanza massima di 450 m.
    E.4Principal exclusion criteria
    - Pulmonary arterial hypertension (PAH) not fulfilling the
    criteria of ES as described in inclusion criterion 3 (e.g.,complex cardiac defects, single ventricle, and patent ductus arteriosus).
    - Known moderate-to-severe restrictive (i.e., total lung capacity [TLC] < 60% of predicted value) or obstructive lung
    disease (i.e., forced expiratory volume in one second [FEV1]
    < 80 % of predicted, with FEV1 / forced vital capacity [FVC] < 70%).
    - Down Syndrome
    - Treatment with phosphodiesterase-5 (PDE-5) inhibitors or prostanoids within 1 month prior to Randomization.
    - Treatment with endothelin receptor antagonists (ERAs) within 1 month prior to Randomization.
    - Subjects who initiated diuretics within 1 week prior to Randomization or subjects whose diuretic treatment has not been stable within 1 week prior to Randomization.
    - Subjects being considered for an organ transplant.
    - Ipertensione Arteriosa Polmonare (PAH) che non soddisfa i criteri della Sindrome di Eisenmenger come descritto nel criterio di inclusione 3 (per esempio, difetti cardiaci complessi, ventricolo unico e dotto arterioso pervio).
    - Nota malattia polmonare restrittiva (ossia, capacità polmonare totale [TLC] &lt; 60% del valore predetto) o ostruttiva (ossia, volume espiratorio forzato in un secondo [FEV1] &lt; 80 % del valore predetto, con FEV1 / capacità vitale forzata [FVC] &lt; 70%) da moderata a grave.
    - Sindrome di Down.
    - Trattamento con inibitori della fosfodiesterasi di tipo 5 (PDE-5) o prostanoidi nel mese precedente la Randomizzazione.
    - Trattamento con antagonisti del recettore dell'endotelina (ERAs) nel mese precedente la Randomizzazione.
    - Soggetti che hanno iniziato l'assunzione di diuretici entro 1 settimana prima della Randomizzazione o soggetti il cui trattamento diuretico non è stato stabile nella settimana precedente la Randomizzazione.
    - Soggetti in lista per trapianto di organo.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline to Week 16 in exercise capacity, as
    measured by the 6MWD.
    Variazione dal basale alla Settimana 16 della capacità di esercizio, misurata con la 6MWD.
    E.5.1.1Timepoint(s) of evaluation of this end point
    - Baseline
    - Week 16
    - Baseline
    - Settimana 16
    E.5.2Secondary end point(s)
    Change from baseline to Week 16* in:
     WHO functional class,
     Dyspnea (assessed by the Borg dyspnea index),
     QoL (assessed by the SF-36 questionnaire).
    Variazione dal basale alla Settimana 16* per:
    • Classe funzionale WHO
    • Dispnea (valutata con la scala di Borg)
    • QoL (valutata con il questionario SF-36).
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Baseline
    - Week 16
    - Baseline
    - Settimana 16
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability; hemodynamic for sub-study only
    tollerabilità; emodinamica per il solo sottostudio
    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. 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA37
    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
    Russian Federation
    South Africa
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months14
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months18
    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.1.1Number of subjects for this age range: 0
    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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 91
    F.4.2.2In the whole clinical trial 220
    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)
    An Open Label extension study will be considered for subjects who
    complete the 16 weeks of double-blind treatment, as scheduled and for
    subjects who prematurely discontinue study drug, provided they return
    to the site for Visit 6a / Week 16.
    Uno studio di estensione in aperto sarà considerato per i soggetti che completano la Settimana 16 del trattamento in doppio cieco come previsto e per i soggetti che interrompono prematuramente il farmaco in studio purchè ritornino al centro per la Visita 6a/Settimana 16.
    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 Decision2013-02-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-01-15
    P. End of Trial
    P.End of Trial StatusCompleted
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