Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)

Inclusion Criteria:

• Signed and dated informed consent form (ICF)

• Confirmed diagnosis of symptomatic PAH in WHO FC II or III

• Symptomatic PAH belonging to one of the following subgroups of WHO Group 1 pulmonaryhypertension:

• Idiopathic

• Heritable

• Drug- or toxin-induced

• Associated with connective tissue disease, HIV infection, portal hypertensionor congenital heart disease with simple systemic-to-pulmonary shunt withpersistent pulmonary hypertension documented by a right heart catheterization (RHC) ≥ 1 year after surgical repair

• PAH diagnosis confirmed by hemodynamic evaluation at rest (through central reading),evaluated within 5 weeks prior to randomization:

• Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, AND

• Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolicpressure (LVEDP) ≤ 15 mmHg, AND

• Pulmonary vascular resistance (PVR) ≥ 3 WU (i.e., ≥ 240 dyn∙sec∙cm-5)

• Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH. (Participants for whom no vasoreactivity test was performed at diagnosis can beeligible if currently treated with PAH therapy for more than 3 months and PAHdiagnosis confirmed by hemodynamic evaluation at least 3 months after introductionof their PAH therapy).

• Currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 monthsprior to baseline RHC, within the prespecified doses in the study protocol or nohistory of PAH-specific treatment

• Participant able to perform the 6MWT with a minimum distance of 100 m and maximumdistance of 450 m at Screening

• A woman of childbearing potential must:

• have negative serum pregnancy test at Screening and a negative urine pregnancytest at Randomization

• agree to undertake monthly urine pregnancy tests during the study and up to atleast 30 days after study treatment discontinuation

• agree to follow the contraception scheme from Screening up to at least 30 daysafter study treatment discontinuation

Exclusion Criteria:

• Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form ofprostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infusedroutes) in the 3-month period prior to start of treatment

• Treatment with combination therapy of ERA and PDE-5i in the 3-month period prior tostart of treatment or history of intolerance to ERA and PDE-5i combination therapy

• Hypersensitivity to any of the study treatments or any excipient of theirformulations

• Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer in the 1-month periodprior to start of treatment

• Treatment with a strong CYP3A4 inhibitor or a moderate dual CYP3A4/CYP2C9 inhibitoror co-administration of a combination of moderate CYP3A4 and moderate CYP2C9inhibitors in the 1-month period prior to start of treatment

• Treatment with doxazosin

• Treatment with any form of organic nitrate, either regularly or intermittently

• Diuretic treatment initiated or dose changed within 1 week prior to the RHC or startof treatment

• Treatment with another investigational drug in the 3-month period prior to start oftreatment

• Body mass index (BMI) > 40 kg/m2 at Screening

• Known presence of three or more of the following risk factors for heart failure withpreserved ejection fraction at Screening:

• BMI > 30 kg/m2

• Diabetes mellitus of any type

• Essential hypertension (even if well controlled)

• Coronary artery disease, i.e. history of stable angina or known more than 50%stenosis in a coronary artery or history of myocardial infarction or history ofor planned coronary artery bypass grafting and/or coronary artery stenting

• Known presence of moderate or severe obstructive lung disease any time prior toScreening as specified in study protocol

• Known presence of moderate or severe restrictive lung disease any time prior toScreening as specified in study protocol

• Clinically significant aortic or mitral valve disease; pericardial constriction;restrictive or congestive left-sided cardiomyopathy; life-threatening cardiacarrhythmias; significant left ventricular dysfunction; or left ventricular outflowobstruction, in the opinion of the investigator

• Known permanent atrial fibrillation, in the opinion of the investigator

• Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism)

• Documented pulmonary veno-occlusive disease

• Hemoglobin < 100 g/L (<10 g/dL) at Screening

• Known severe hepatic impairment as specified in study protocol

• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 ×upper limit of normal (ULN) at Screening

• Severe renal impairment at Screening as specified in study protocol

• Systemic hypotension at Screening or Randomization and systemic hypertension atScreening as specified in study protocol

• Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last 26 weeks prior to Screening

• Known bleeding disorder, in the opinion of the investigator

• Loss of vision in one or both eyes because of non-arteritic anterior ischemic opticneuropathy

• Hereditary degenerative retinal disorders, including retinitis pigmentosa

• History of priapism, conditions that predispose to priapism (example, sickle cellanemia, multiple myeloma, or leukemia) or anatomical deformation of the penis (example, angulation, cavernosal fibrosis, or Peyronie's disease)

• Difficulty swallowing large pills/tablets that would interfere with the ability tocomply with study treatment regimen

• Any planned surgical intervention (including organ transplant) during thedouble-blind treatment period, except minor interventions

• Exercise training program for cardiopulmonary rehabilitation in the 12-week periodprior to start of treatment, or planned to be started during the double-blind periodof the study

• Pregnant, planning to become pregnant or lactating

• Any known factor or disease that might interfere with treatment adherence, fullparticipation in the study or interpretation of the results as judged by theinvestigator (e.g., drug or alcohol dependence etc.)

• Known concomitant life-threatening disease with a life expectancy less than (<) 12months

• Calcium channel blocker treatment initiated, or dose changed within 3 months priorto right heart catheterization (RHC) at screening