A Pulmonary Arterial Hypertension Study With Macitentan to Validate the PAH-SYMPACT™ in France, Italy and Spain

Inclusion Criteria:

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

2. Patients with symptomatic PAH in WHO Functional Class (FC) II or III.

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

4. Idiopathic, or,

5. Heritable, or,

6. Drug or toxin induced, or,

7. Associated with one of the following: i. Connective tissue disease, ii. Congenital heart disease with simplesystemic-to-pulmonary shunt at least 1 year after surgical repair, iii. HIV infection.

8. Documented hemodynamic diagnosis of PAH by right heart catheterization - performed atany time prior to Screening showing:

9. Resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and,

10. Resting pulmonary vascular resitance (PVR) > 240 dyn.s.cm-5 and,

11. Pulmonary capillary wede pressure (PCWP) or left ventricular end diastolicpressure (LVEDP) ≤ 15 mmHg.

12. 6-minute walk distance (6MWD) ≥ 150 m at Screening.

13. Able to fluently speak and read the local language.

14. Men or women aged 18-80; women of childbearing potential (as defined below) must:

15. Have a negative serum pregnancy test at Screening and a negative urine pregnancytest at Baseline and agree to perform monthly serum pregnancy tests, and,

16. Agree to use two reliable methods of contraception in parallel, from ScreeningVisit 1 until 1 month after study drug discontinuation (see details below).

• A female is considered to have childbearing potential unless she meets atleast one of the following criteria:

• Previous bilateral salpingo and/or oophorectomy, or hysterectomy.

• Premature ovarian failure confirmed by a specialist.

• Pre-pubescence, XY genotype, Turner syndrome, uterine agenesis.

• Postmenopausal, defined as 12 consecutive months with no menses withoutan alternative medical cause.

• Of the two contraceptive methods that must be used, one must be from Group 1, and one must be from Group 2, defined as follows:

• Group 1: Oral, implantable, transdermal or injectable hormonalcontraceptives, intrauterine devices, female sterilization (tuballigation or non surgical sterilization, e.g., permanent contraceptionwith Essure procedure), or partner's sterilization (vasectomy). If ahormonal contraceptive is chosen from this group, it must be taken forat least 1 month prior to enrollment. Alternatively, if the Essureprocedure is chosen as a contraceptive method, a hysterosalpingogrammust have been performed to confirm correct location of themicroinserts and tubal occlusion (as per manufacturer'srecommendations).

• Group 2: Female or male condoms, diaphragm or cervical cap, any of themin combination with a spermicide.

• Sexual abstinence, rhythm methods, or contraception by the partner alone arenot considered as acceptable methods of contraception for this study.

Exclusion Criteria:

1. Known moderate-to-severe obstructive lung disease (i.e., forced expiratory volume inone second [FEV1] < 80 % of predicted, with FEV1 / forced vital capacity [FVC] < 70%)or known significant chronic lung disease diagnosed by chest imaging (e.g.,interstitial lung disease, emphysema).

2. Known moderate-to-severe restrictive lung disease (i.e., total lung capacity [TLC] < 60% of predicted value).

3. Hemoglobin < 100g/L at Screening.

4. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 Xupper limit of the normal range (ULN) at Screening.

5. Patients undergoing dialysis.

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. Treatment with ERAs within 3 months prior to Visit 2, or scheduled to receive any ofthese compounds, other than macitentan, during the trial.

10. 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 thetrial.

11. Treatment with soluble guanylate cyclase stimulator (riociguat) within 3 months priorto Visit 2, or scheduled to receive riociguat during the trial.

12. Patients who changed the dose of or discontinued phosphodiesterase type-5 inhibitor (PDE5i), inhaled prostacyclin analogues, or calcium channel blockers within 3 monthsprior to Visit 2.

13. Initiation of diuretics within 1 week prior to the Baseline period.

14. Patients on oral diuretics in whom the dose has not been stable for at least 1 weekprior to the Baseline period.

15. Treatment with cytochrome P4500 (CYP) 3A inducers within 4 weeks prior to Visit 2.

16. Recently started (< 8 weeks prior to Visit 2) or planned cardio-pulmonaryrehabilitation program based on exercise.

17. Females who are lactating or pregnant (positive Screening or Baseline pregnancy test)or plan to become pregnant during the study.

18. Known hypersensitivity to macitentan or its excipients or drugs of the same class.

19. Treatment with another investigational drug within 3 months prior to Visit 2.

20. Any known factor or disease that might interfere with treatment compliance, studyconduct or interpretation of the results such as drug or alcohol dependence orpsychiatric disease.