Clinical Study of Macitentan in Patients With Pulmonary Arterial Hypertension to Psychometrically Validate the PAH-SYMPACT Instrument

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