The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension

Inclusion criteria

• Signed informed consent prior to any study-mandated procedure.
• Male or female ≥ 18 and ≤ 75 years of age at screening.
• Initial PAH diagnosis < 6 months prior to enrollment.
• RHC performed between Day -28 and Day 1, meeting all the following criteria:

• Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg.
• Pulmonary artery wedge pressure or left ventricular end-diastolic pressure ≤ 15 mmHg.
• PVR ≥ 480 dyn•sec/cm5 (≥ 6 Wood Units).
• Negative vasoreactivity test mandatory in idiopathic, heritable, and drug/toxin induced PAH (at this or a previous RHC).
• Symptomatic PAH belonging to one of the following subgroups:

• Idiopathic.
• Heritable.
• Drug or toxin induced.
• Associated with one of the following: connective tissue disease; HIV infection; congenital heart disease.
• 6-minute walk distance (6MWD) ≥ 50 m at screening.
• Women of childbearing potential must not be pregnant, must perform regular pregnancy tests, and use reliable contraception.

Exclusion criteria

• Any PAH-specific drug therapy at any time.
• Cardio pulmonary rehabilitation program based on exercise (planned, or started ≤ 12 weeks prior to Day 1).
• Body mass index (BMI) > 40 kg/m2 at screening.
• Presence of three or more of the following risk factors for heart failure with preserved ejection fraction at screening:

• BMI > 30 kg/m2.
• Diabetes mellitus of any type.
• Essential hypertension.
• Coronary artery disease, i.e., any of the following:

• History of stable angina or
• More than 50% stenosis in a coronary artery (by coronary angiography) or
• History of myocardial infarction or
• History of or planned coronary artery bypass grafting and/or coronary artery stenting.
• Acute myocardial infarction ≤ 12 weeks prior to screening.
• Stroke ≤ 12 weeks prior to screening.
• Known permanent atrial fibrillation.
• SBP < 90 mmHg at screening or Day 1.
• Ongoing or planned treatment with organic nitrates and/or doxazosin.
• Presence of one or more of the following signs of relevant lung disease at any time up to screening:

• Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% of predicted (eligible only if no or mild interstitial lung disease on computed tomography).
• Forced vital capacity (FVC) < 60% of predicted.
• Forced expiratory volume in one second (FEV1) < 60% of predicted.
• Known or suspected pulmonary veno-occlusive disease (PVOD).
• Documented 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 aspartate aminotransferase (AST) > ULN (assessed by central laboratory at screening); and/or Child-Pugh Class C.
• Serum AST and/or alanine aminotransferase (ALT) > 3 × ULN (assessed by central laboratory at screening).
• Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m2) assessed by central laboratory at screening.
• Ongoing or planned dialysis.
• Hemoglobin < 100 g/L assessed by central laboratory at screening.
• Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).
• Loss of vision in one or both eyes because of non-arteritic ischemic optic neuropathy (NAION).
• Treatment with strong inducers of cytochrome P450 3A4 (CYP3A4; e.g., carbamazepine, rifampin, rifampicin, rifabutin, rifapentin, phenobarbital, phenytoin, and St. John's wort) ≤ 28 days prior to Day 1.
• Treatment with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) and/or strong inhibitors of CYP2C8 (e.g., gemfibrozil) ≤ 28 days prior to Day 1.
• Treatment with another investigational drug (planned, or taken ≤ 12 weeks prior to Day 1).
• Hypersensitivity to any of the 3 study treatments or any excipient of their formulations.
• Pregnancy, breastfeeding, or intention to become pregnant during the study.
• Concomitant life-threatening disease with a life expectancy < 12 months.
• Alcohol abuse.
• Any factor or condition likely to affect protocol compliance of the subject, as judged by the investigator.