E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical 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 |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058554 |
E.1.2 | Term | Eisenmenger's syndrome |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to demonstrate that macitentan improves exercise capacity in comparison with placebo in subjects with Eisenmenger Syndrome |
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E.2.2 | Secondary 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). |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
"Hemodynamic sub-study", version 1.GBR.A dated 23 October 2012:
Exploratory objective to evaluate the effects of macitentan in comparison with placebo on hemodynamic parameters (in a sub-set of subjects). |
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E.3 | Principal inclusion criteria |
- 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. |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline to Week 16 in exercise capacity, as measured by the 6MWD. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability.
Hemodynamic for sub-study only |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |