Study of Macitentan (ACT-064992) on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension

Inclusion Criteria:

1. Signed informed consent prior to initiation of any study mandated procedure.

2. Patients with symptomatic pulmonary arterial hypertension (PAH) in modified World
Health Organization (WHO) functional class II to IV.

3. Patients with the following types of pulmonary arterial hypertension (PAH) belonging
to groups 1.1 to 1.3 of the Venice classification:

- Idiopathic (IPAH);

- Familial (FPAH); or

- Related to:

- Collagen vascular disease;

- Simple, congenital systemic-to-pulmonary shunts at least 1 year post
surgical repair;

- Human immunodeficiency virus (HIV) infection; or

- Drugs and toxins.

4. PAH diagnosis confirmed by hemodynamic evaluation performed prior to randomization
and showing all of the following:

- Mean pulmonary artery pressure (mPAP) > 25 mmHg at rest;

- Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic
pressure (LVEDP) < 15 mmHg; and

- Pulmonary vascular resistance (PVR) at rest >= 320 dyn×sec/cm^5.

5. 6-minute walk distance (6MWD) >= 50 m.

6. Men or women > 12 years of age (women of childbearing potential must have a negative
pre-treatment serum pregnancy test and must use a reliable method of contraception).

Exclusion Criteria:

1. PAH associated with portal hypertension, thyroid disorders, glycogen storage disease,
Gaucher''s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies,
myeloproliferative disorders or splenectomy.

2. PAH associated with non corrected simple congenital systemic-to-pulmonary shunts, and
combined and complex systemic-to-pulmonary shunts, corrected or non corrected.

3. PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg),
known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis.

4. Persistent pulmonary hypertension of the newborn.

5. Pulmonary Hypertension belonging to groups 2 to 5 of the Venice classification.

6. Moderate to severe obstructive lung disease: forced expiratory volume in 1
second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 65% of predicted value after
bronchodilator administration.

7. Moderate to severe restrictive lung disease: total lung capacity (TLC) < 60% of
predicted value.

8. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.

9. Estimated creatinine clearance < 30 mL/min

10. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5
times the upper limit of normal.

11. Hemoglobin < 75% of the lower limit of the normal range.

12. Systolic blood pressure < 100 mmHg.

13. Acute or chronic physical impairment (other than dyspnea), limiting the ability to
comply with study requirements.

14. Pregnant or breast-feeding.

15. Known concomitant life-threatening disease with a life expectancy < 12 months.

16. Body weight < 40 kg.

17. Any condition that prevents compliance with the protocol or adherence to therapy.

18. Recently started (< 8 weeks prior to randomization) or planned cardio-pulmonary
rehabilitation program based on exercise.

19. Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to
randomization.

20. Systemic treatment within 4 week prior to randomization with cyclosporine A or
tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin
(mTOR) inhibitors).

21. Treatment with cytochrome P3A (CYP3A) inducers within 4 weeks prior to randomization

22. Known hypersensitivity to drugs of the same class as the study drug, or any of their
excipients.

23. Planned treatment, or treatment, with another investigational drug within 1 month
prior to randomization.