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    Summary
    EudraCT Number:2012-003335-33
    Sponsor's Protocol Code Number:AC-055-305
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-01-31
    Trial results View 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 ConcernedGermany - BfArM
    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.
    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 enough to be used for treatment of Eisenmenger syndrome.
    A.3.2Name or abbreviated title of the trial where available
    MAESTRO : MAcitentan in Eisenmenger Syndrome To RestOre exercise capacity
    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.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 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.5.3.4CountrySwitzerland
    B.5.6E-mailmedinfo@actelion.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 Opsumit
    D.2.1.1.2Name of the Marketing Authorisation holderACTELION Pharmaceuticals Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/11/909
    D.3 Description of the IMP
    D.3.1Product namemacitentan
    D.3.2Product code ACT-064992
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmacitentan
    D.3.9.1CAS number 441798-33-0
    D.3.9.2Current sponsor 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.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
    Eisenmenger Syndrome
    E.1.1.1Medical condition in easily understood language
    Condition caused by a defect in the heart or in a blood vessel connecting to the heart that affects blood flow between the heart and the lungs
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10058554
    E.1.2Term Eisenmenger's syndrome
    E.1.2System Organ Class 100000004850
    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 is to demonstrate that macitentan improves exercise capacity in comparison with placebo in subjects with Eisenmenger Syndrome
    E.2.2Secondary objectives of the trial
    The secondary objectives are to evaluate the effects of macitentan in comparison with placebo on:
    - WHO functional class
    - Dyspnea (assessed by the Borg dyspnea index),
    - Quality of Life (QoL; assessed by the Short-Form 36 [SF-36] questionnaire).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Subjects:
    • not participating in the hemodynamic sub-study: males or females ≥ 12 years of age.
    • participating in the hemodynamic sub-study: males or females ≥ 18 years of age.

    - Subjects (including those with Down Syndrome (DS)) with confirmed ES (European Society of Cardiology [ESC] and the European Respiratory Society [ERS] guidelines):
    a) Established by echocardiography as:
    • Large congenital shunting defect at atrial, ventricular or arterial level*
    • and right to left shunt or bi-directional shunt with prevalent right to left direction.
    b) Resting peripheral oxygen saturation (SpO2) ≤ 90% and > 70% (pulse oximetry, room air).
    The lower limit is 65% if a subject is living at an altitude greater than 2500 m above sea level.

    *Subjects with any of the following open defects are eligible for the study either as an isolated defect or in combination:
    • atrial septal defect (ASD)
    • ventricular septal defect (VSD)
    • partial or complete atrioventricular septal defect (AVSD)
    • patent ductus arteriosus (PDA)
    • aortopulmonary window (AP window)
    • total or partial anomalous pulmonary venous return (TAPVR, PAPVR)
    The defects may be either unoperated or previously palliated surgically (provided significant residual defect remains).
    The Steering Committee will review the echocardiography data of all subjects (main study and sub study) to confirm eligibility prior to Randomization.

    - Subjects with the following findings at 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 reliably perform the 6-minute walk test (6MWT) with a minimum distance of 50 m and a maximum distance of 450 m.
    E.4Principal exclusion criteria
    - Main study and hemodynamic sub-study: Any of the following conditions previously known or identified via cardiac catheterization or echocardiography:
    • Pulmonary arterial or venous stenosis > 25% size of native pulmonary artery (PA)
    • Severe tricuspid regurgitation in the setting of left to right shunt at the ventricular or atrial level
    • Greater than mild tricuspid stenosis
    • Intracavitary RV outflow obstruction
    • Greater than mild mitral stenosis
    • Intracavitary LVoutflow obstruction
    • Subvalvular or supravalvular aortic stenosis
    • Aortic coarctation
    • Greater than moderate mitral regurgitation
    • Recognized extracardiac systemic venous collaterals to the pulmonary venous circulation
    • Recognized hepatic wedge pressure-inferior vena cava pressure gradient > 12 mmHg
    • PCWP "v" waves >20 mmHg
    • Tetralogy of Fallot
    • Truncus arteriosus
    • Interrupted aortic arch
    • Transposition of the great arteries
    • Single ventricle defects: absent AV connection (mitral or tricuspid atresia), double inlet AV connections left or right ventricle, functional univentricular heart (unbalanced AVSD, hypoplastic RV, double outlet RV), hypoplastic left heart syndrome
    • Ebstein's anomaly
    • Severe aortic regurgitation
    • Pulmonary atresia
    • PAPVR or TAPVR, ONLY if there is lung hypoplasia or if documentation confirming the absence of lung hypoplasia does not exist.

    For subjects participating in the hemodynamic sub-study the following will also be considered exclusion criteria:
    • SVC stenosis > 25% size of native vessel.
    • PDA, aorto-pulmonary window, TAPVR, PAPVR, or ASD sinus venosus with anomalous pulmonary veins.
    • Down Syndrome

    - Subjects with deterioration of their clinical status within 3 months prior to Screening or during the Screening period.

    - 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 value, and with FEV1 / forced vital capacity [FVC] < 70%).

    - Treatment with prostanoids within 1 month prior to Randomization.

    - Subjects who initiated a PDE-5 inhibitor within 1 month prior to Randomizationor those on a PDE-5 inhibitor for whom the dose has not been stable 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 for at least 1 week prior to Randomization.

    - Subjects being considered for an organ transplant.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline to Week 16 in exercise capacity, as measured by the 6MWD.
    E.5.1.1Timepoint(s) of evaluation of this end point
    - Baseline
    - Week 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).
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Baseline
    - Week 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
    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 EEA45
    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
    Austria
    Belgium
    Bulgaria
    Canada
    Chile
    China
    Czech Republic
    France
    Germany
    Hungary
    India
    Israel
    Italy
    Malaysia
    Mexico
    Netherlands
    Philippines
    Poland
    Portugal
    Romania
    Russian Federation
    Serbia
    Singapore
    South Africa
    Spain
    Taiwan
    Turkey
    United Kingdom
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 15
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 15
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 190
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2013-01-31. Yes
    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
    Down Syndrome patients (DS patients who are not capable of providing full informed consent must provide assent)
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Children (12 to 17 years old)
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    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.
    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 Decision2013-02-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-02-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-12-01
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