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

Inclusion criteria

• Signed informed consent prior to initiation of any study mandated procedure
• Patients with symptomatic PAH in World Health Organization (WHO) Functional Class (FC) II to IV
• Patients with PAH belonging to one of the following subgroups of the Dana Point Clinical Classification Group 1:

• Idiopathic, or
• Heritable, or
• Drug or toxin induced, or
• 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

• Documented hemodynamic diagnosis of PAH by right heart catheterization - performed at any time prior to Screening showing:

• Resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and
• Resting pulmonary vascular resistance (PVR) > 240 dyn•s•cm-5 and
• Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg
• 6-minute walk distance (6MWD) ≥ 150 m at Screening
• Able to fluently speak and read English
• 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
• For patients on oral diuretics, stable doses for at least 4 weeks prior to Visit 2
• Men or women aged 18 or older

• 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)
• 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

• 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
• Moderate to severe restrictive lung disease: total lung capacity < 60% of predicted value
• Hemoglobin < 75% of the lower limit of the normal range at screening
• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of normal (ULN) at screening
• Estimated creatinine clearance < 30 mL/min at screening
• Systolic blood pressure (SBP) < 90 mmHg at screening
• Body weight < 40 kg at screening
• Known concomitant life-threatening diseases with a life expectancy of < 12 months
• Any condition that prevents compliance with the protocol or adherence to therapy
• 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
• 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
• Treatment with riociguat within 3 months prior to Visit 2, or scheduled to receive riociguat during the trial
• Treatment with strong cytochrome P450 (CYP) 3A4 inducers or inhibitors within 4 weeks prior to Visit 2
• Recently started (< 8 weeks prior to Visit 2) or planned cardio-pulmonary rehabilitation program based on exercise
• Females who are lactating or pregnant (positive Screening or Baseline pregnancy test) or plan to become pregnant during the study
• Known hypersensitivity to macitentan or its excipients or drugs of the same class
• Treatment with another investigational drug within 3 months prior to Visit 2
• 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