Clinical Study to Evaluate the Effects of Macitentan on Exercise Capacity in Subjects With Eisenmenger Syndrome

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 Eisenmenger Syndrome
[ES] (European Society of Cardiology [ESC] and the European Respiratory Society [ERS]
guidelines):

1. 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.

2. 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:

- 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 the 6-minute walk test (6MWT) with a minimum
distance of 50 m and a maximum distance of 450 m.

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) or
pulmonary vein

- 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 LV outflow 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 mm Hg

- PCWP "v" waves >20 mmHg

- Tetralogy of Fallot

- Truncus arteriosus

- Interrupted aortic arch

- Transposition of 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, AP 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 Randomization or
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