The AC-055-302/SERAPHIN study will be an event-driven Phase III study, comparing two different doses of ACT-064992 (3 and 10 mg) vs placebo in patients with symptomatic PAH. The main study objective is to demonstrate that ACT-064992 prolongs time to the first morbidity or mortality event, and to evaluate the benefit/risk profile of ACT-064992 in the treatment of patients with symptomatic PAH.

• Drug: ACT-064992
  Tablet, 3 mg dosage, once daily
• Drug: ACT-064992
  Tablet, 10 mg dosage, once daily
• Drug: Placebo
  Matching ACT-064992 placebo, once daily

• 1: Experimental
  ACT-064992 tablet, 3 mg, once daily
  Intervention: Drug: ACT-064992
• 2: Experimental
  ACT-064992 tablet, 10 mg, once daily
  Intervention: Drug: ACT-064992
• 3: Placebo Comparator
  Matching ACT-064992 placebo, once daily
  Intervention: Drug: Placebo

Inclusion Criteria:

1. Signed informed consent prior to initiation of any study mandated procedure.
2. Patients with symptomatic pulmonary arterial hypertension (PAH) in modified WHO functional class II to IV.

3. Patients with the following types of 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;
     • 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/cm5.
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 mTOR inhibitors).
21. Treatment with 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.