SYMPHONY

A multi-center, open-label, single-arm, Phase 3b study of macitentan in patients with Pulmonary Arterial Hypertension to psychometrically validate the PAH-SYMPACT instrument

Inclusion Criteria:

1.  Patients with symptomatic PAH in WHO functional Class II to IV

2.  Patients with PAH belonging to Dana Point Clinical Classification Group 1 (idiopathic; heritable; drug or toxin induced; connective tissue disease; congenital heart disease; HIV)

3.  Resting mPAP ≥25 mmHg and Resting PVR >240 dyn·s·cm and PCWP or LVEDP ≤15 mmHg

4.  6MWD ≥ 150m at screening

5.  For patient on PDE5i, inhaled prostacyclin analogues or calcium channel blockers, stable does for at least 3 months prior to study enrollment

6.  For patients on oral diuretics, stable doses for at least 4 weeks prior to study enrollment

Exclusion Criteria:

1.  Moderate to severe obstructive lung disease:  FEV1/FVC < 70% and FEV1 <65%

2.  Moderate to severe restrictive lung disease:  TLC < 60%

3.  Moderate to severe hepatic impairment

4.  Hemoglobin <75% of lower limit of normal range

5.  Serum AST and/or ALT > 3 x ULN at screening

6.  Estimated creatine clearance < 30 mL/min at screening

7.  SBP < 100 mmHG at screening

8.  Body weight < 40 kg at screening

9.  Known concomitant life threatening diseases with life expectancy of  < 12 months

10.  Treatment with ERA within 3 months of study enrollment

11.  Treatment with IV of subcutaneous prostacyclin or prostacyclin analogues within 3 months prior to study enrollment, or are scheduled to receive any of these compounds during the trial

12.  Treatment with riociguat within 3 months prior to study enrollment, or are scheduled to receive during the trial

13.  Treatment with CYP3A inducers within 4 weeks of study enrollment

14.  Recently started (< 8 weeks) or planned cardio-pulmonary rehab program

15.  Females who are lactating or pregnant 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 of study enrollment

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