The study evaluates the effect of macitentan on right ventricular and hemodynamic properties in patients with symptomatic pulmonary arterial hypertension. Patients are treated with macitentan for 1 year. Patients undergo right heart catheterization (RHC) at baseline and Week 26. They also undergo cardiac magnetic resonance imaging (MRI) at baseline, Week 26 and Week 52. Safety is monitored throughout the study. The study has three stub-studies. Each patient can participate in no sub-study or in one sub-study. The sub-studies are: (1) metabolism sub-study (with PET-MR scans); (2) biopsy sub-study (biopsies taken during the RHC); (3) Echo sub-study.

Inclusion Criteria:

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

2. Symptomatic pulmonary arterial hypertension (PAH)

3. World Health Organization (WHO) Functional Class (FC) I to III

4. PAH etiology belonging to one of the following groups according to Nice classification:

   • Idiopathic PAH
   • Heritable PAH
   • Drug- and toxin-induced PAH
   • PAH associated with congenital heart diseases: only simple (atrial septal defect, ventricular septal defect, patent ductus arteriosus) congenital systemic to pulmonary shunts at least 2 year post surgical repair

5. Hemodynamic diagnosis of PAH confirmed by right heart catheterization (RHC) during screening showing:

   • mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and

   • PCWP (pulmonary capillary wedge pressure) or left ventricular end diastolic pressure (LVEDP) ≤ 12 mmHg and pulmonary vascular resistance (PVR) ≥ 4 Wood Units (WU) (320 dyn.sec.cm-5) or
   • 12 mmHg ≤ PCWP or LVEDP ≤ 15 mmHg and PVR ≥ 6WU (480 dyn.sec.cm-5)

6. 6-minute walk distance (6MWD) ≥ 150 m during screening

7. For patients treated with oral diuretics, treatment dose must have been stable at least 1 month prior to RHC during the screening period

8. For patients treated with phosphodiesterase type-5 (PDE-5) inhibitors, treatment dose must have been stable at least 3 months prior to RHC during the screening period

9. For patients treated with beta blockers, treatment dose must have been stable at least 1 month prior to the RHC during the screening period

10. Men or women ≥18 and < 65 years

11. Women of childbearing potential (defined in protocol) must:

    • Have a negative serum pregnancy test during screening and a negative urine pregnancy test on Day 1, and
    • Agree to use reliable methods of contraception (defined in protocol) from screening up to 30 days after study treatment discontinuation, and
    • Agree to perform monthly pregnancy tests up to 30 days after study treatment discontinuation

Exclusion Criteria:

1. Body weight < 40 kg

2. Body mass index (BMI) > 35kg/m2. For patients with 30kg/m2 < BMI < 35kg/m2, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient.

3. Pregnancy, breastfeeding or intention to become pregnant during the study

4. Recently started (< 8 weeks prior to informed consent signature) or planned cardio-pulmonary rehabilitation program

5. Known concomitant life-threatening disease with a life expectancy < 12 months

6. Any condition likely to affect protocol or treatment compliance

7. Hospitalization for PAH within 3 months prior to informed consent signature

8. Left atrial volume indexed for body surface area ≥ 43mL/m2 by echocardiography or cardiac MRI

9. Valvular disease grade 2 or higher

10. History of pulmonary embolism or deep vein thrombosis

11. Documented moderate to severe chronic obstructive pulmonary disease

12. Documented moderate to severe restrictive lung disease

13. Historical evidence of significant coronary artery disease established by:

    • History of myocardial infarction or
    • More than 50% stenosis in a coronary artery (by percutaneous coronary intervention or angiography) or
    • Elevation of the ST segment on electrocardiogram or
    • History of coronary artery bypass grafting or
    • Stable angina

14. Diabetes mellitus

15. Moderate to severe renal insufficiency (calculated creatinine clearance < 60 mL/min/1.73 m2)

16. Cancer

17. Systolic blood pressure < 90 mmHg

18. Severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 × upper limit of the normal range (ULN) accompanied by an aspartate aminotransferase (AST) elevation > ULN at Screening.

19. Hemoglobin < 100g/L

20. AST and/or alanine aminotransferase (ALT) > 3× ULN

21. Need for dialysis

22. Responders to acute vasoreactivity test based on medical history

23. Prior use of endothelin receptor antagonists (ERAs), stimulators of soluble guanylate cyclase or prostacyclin or prostacyclin analogues

24. Treatment with strong inducers of cytochrome P450 isozyme 3A4 (CYP3A4) within 4 weeks prior to study treatment initiation (e.g., carbamazepine, rifampicin, rifabutin, phenytoin and St. John's Wort)

25. Treatment with strong inhibitors of CYP3A4 within 4 weeks prior to study treatment initiation (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir)

26. Treatment with another investigational drug (planned, or taken within the 3 months prior to study treatment initiation).

27. Hypersensitivity to any ERA or any excipients of the formulation of macitentan (lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, polyvinyl alcohol, polysorbate, titanium dioxide, talc, xanthan gum, and lecithin soya)

28. Claustrophobia

29. Permanent cardiac pacemaker, automatic internal cardioverter

30. Metallic implant (e.g., defibrillator, neurostimulator, hearing aid, permanent use of infusion device)

31. Atrial fibrillation, multiple premature ventricular or atrial contractions, or any other condition that would interfere with proper cardiac gating during MRI.

32. For patients enrolling in the metabolism sub-study only: glucose intolerance

33. For patients enrolling in the biopsy sub-study only: PAH etiology belonging to Nice classification 1.4.4: PAH associated with congenital heart diseases

If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.