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

Inclusion criteria

• Signed informed consent prior to initiation of any study mandated procedure.
• Patients with symptomatic pulmonary arterial hypertension (PAH) in modified World Health Organization (WHO) functional class II to IV.
• 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.
• 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.
• 6-minute walk distance (6MWD) >= 50 m.
• 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

• PAH associated with portal hypertension, thyroid disorders, glycogen storage disease, Gaucher''s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy.
• PAH associated with non corrected simple congenital systemic-to-pulmonary shunts, and combined and complex systemic-to-pulmonary shunts, corrected or non corrected.
• PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis.
• Persistent pulmonary hypertension of the newborn.
• Pulmonary Hypertension belonging to groups 2 to 5 of the Venice classification.
• 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.
• Moderate to severe restrictive lung disease: total lung capacity (TLC) < 60% of predicted value.
• Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
• Estimated creatinine clearance < 30 mL/min
• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal.
• Hemoglobin < 75% of the lower limit of the normal range.
• Systolic blood pressure < 100 mmHg.
• Acute or chronic physical impairment (other than dyspnea), limiting the ability to comply with study requirements.
• Pregnant or breast-feeding.
• Known concomitant life-threatening disease with a life expectancy < 12 months.
• Body weight < 40 kg.
• Any condition that prevents compliance with the protocol or adherence to therapy.
• Recently started (< 8 weeks prior to randomization) or planned cardio-pulmonary rehabilitation program based on exercise.
• Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to randomization.
• Systemic treatment within 4 week prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin (mTOR) inhibitors).
• Treatment with cytochrome P3A (CYP3A) inducers within 4 weeks prior to randomization
• Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients.
• Planned treatment, or treatment, with another investigational drug within 1 month prior to randomization.