REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension

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