SYMPHONY is prospective, multi-center, open-label, single-arm, Phase 3b psychometric validation study of the PAH-SYMPACT, a new quality of life questionnaire for patients with pulmonary arterial hypertension. Patients will be in the study for 5 1/2 months, 4 months of which they will receive macitentan, 10 mg, once daily.

The primary objectives are to demonstrate the final content validity of the PAH SYMPACT instrument, to demonstrate the psychometric characteristics of reliability and construct validity of the PAH-SYMPACT instrument, and to demonstrate the ability of the PAH SYMPACT instrument to detect change. The secondary objective is to assess the safety of macitentan in patients with pulmonary arterial hypertension. The exploratory objective is to explore the effects of macitentan on PAH symptoms and their impact (as measured by the PAH-SYMPACT) in patients with pulmonary arterial hypertension.

Inclusion Criteria:

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

2. Patients with symptomatic PAH in World Health Organization (WHO) Functional Class (FC) II to IV

3. Patients with PAH belonging to one of the following subgroups of the Dana Point Clinical Classification Group 1:

   1. Idiopathic, or
   2. Heritable, or
   3. Drug or toxin induced, or
   4. Associated with one of the following:

   i. Connective tissue disease ii. Congenital heart disease with simple systemic-to-pulmonary shunt at least one year after surgical repair iii. HIV infection

4. Documented hemodynamic diagnosis of PAH by right heart catheterization - performed at any time prior to Screening showing:

   1. Resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and
   2. Resting pulmonary vascular resistance (PVR) > 240 dyn•s•cm-5 and
   3. Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg

5. 6-minute walk distance (6MWD) ≥ 150 m at Screening

6. Able to fluently speak and read English

7. For patients on phosphodiesterase type-5 inhibitors (PDE5i), inhaled prostacyclin analogues, or calcium channel blockers, stable doses for at least 3 months prior to Visit 2

8. For patients on oral diuretics, stable doses for at least 4 weeks prior to Visit 2

9. Men or women aged 18 or older

   1. A woman is considered to be of childbearing potential unless she:

      • Has not yet entered puberty, or
      • Does not have a uterus, or
      • Has gone through menopause (has not had a period for at least 12 months for natural reasons, or who has had their ovaries removed)

   2. A women of childbearing potential is eligible only if she meets both criteria below:

      • Has a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline and agree to perform monthly urine pregnancy tests, and
      • Agrees to use two methods of contraception (one method for patients with a progesterone implant or an intrauterine device or tubal sterilization) from the Screening Visit 1 until one month after study drug discontinuation

Exclusion Criteria:

1. Moderate to severe obstructive lung disease: forced expiratory volume in one second (FEV1) / forced vital capacity < 70% and FEV1 < 65% of predicted value after bronchodilator administration
2. Moderate to severe restrictive lung disease: total lung capacity < 60% of predicted value
3. Hemoglobin < 75% of the lower limit of the normal range at screening
4. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of normal (ULN) at screening
5. Estimated creatinine clearance < 30 mL/min at screening
6. Systolic blood pressure (SBP) < 90 mmHg at screening
7. Body weight < 40 kg at screening
8. Known concomitant life-threatening diseases with a life expectancy of < 12 months
9. Any condition that prevents compliance with the protocol or adherence to therapy
10. Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to Visit 2, or scheduled to receive any of these compounds, other than macitentan, during the trial
11. Treatment with intravenous or subcutaneous prostacyclin or prostacyclin analogs within 3 months prior to Visit 2, or scheduled to receive any of these compounds during the trial
12. Treatment with riociguat within 3 months prior to Visit 2, or scheduled to receive riociguat during the trial
13. Treatment with strong cytochrome P450 (CYP) 3A4 inducers or inhibitors within 4 weeks prior to Visit 2
14. Recently started (< 8 weeks prior to Visit 2) or planned cardio-pulmonary rehabilitation program based on exercise
15. Females who are lactating or pregnant (positive Screening or Baseline pregnancy test) or plan to become pregnant during the study
16. Known hypersensitivity to macitentan or its excipients or drugs of the same class
17. Treatment with another investigational drug within 3 months prior to Visit 2
18. Any known factor or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease