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 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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10058554 |
E.1.2 | Term | Eisenmenger's syndrome |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 2.HUN.B dated 29 August 2013:
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 and ≤ 70 years of age.
- Subjects with confirmed ES (European Society of Cardiology [ESC] and the European Respiratory Society [ERS] guidelines):
• 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) and including fully repaired patent ductus arteriosus (PDA).
• 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, or subjects with WHO functional class III or IV in whom standard PAH therapy is not feasible or has failed.
- Subjects able to 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 |
- Pulmonary arterial hypertension (PAH) not fulfilling the criteria of ES as described in inclusion criterion 3 (e.g., complex cardiac defects, single ventricle, and unrepaired or partially repaired PDA).
- 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. |
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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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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 |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |