COMMODITIES Trial: Initial Dual Oral Therapy vs Monotherapy in PAH With Cardiovascular Comorbidities

Inclusion criteria

• Initial PAH diagnosis \< 6 months preceding randomisation
• Negative vasoreactivity test
• Treatment-naïve PAH (group 1): idiopathic, heritable, associated with drugs and toxin, associated with connective tissue disease, HIV infection or systemic-to-pulmonary congenital shunt corrected for more than one year
• Meet all of the following hemodynamic criteria by means of a RHC prior to screening:
• mPAP≥25 mmHg and
• PAWP\<15 mmHg and
• with PVR≥3 WU
• Presence of at least two of the following criteria, as listed in the European pulmonary hypertension guidelines:
• History of essential hypertension
• Diabetes mellitus (any type)
• Obesity (defined by a BMI ≥30 kg/m2)
• Coronary heart disease (established by any of the following: history of myocardial infarction, history of percutaneous coronary intervention, angiographic evidence of coronary artery disease (\>50% stenosis in ≥1 vessel), positive ST, previous coronary artery bypass graft, stable angina)
• Participant able to understand the study procedures
• For women of childbearing potential (WOCBP), effective form of contraception\* from screening up to 1 month following discontinuation of the last study treatment
• Affiliation to the french social security regime
• Signed written informed consent

Exclusion criteria

• Porto-pulmonary hypertension
• Uncorrected systemic-to-pulmonary congenital shunt
• Evidence of thromboembolic disease assessed by ventilation perfusion (V/Q) lung scan or CT pulmonary angiography
• Patients listed for lung or heart-lung transplantation at time of screening
• Patients on any PAH-specific drug therapy at any time preceding randomisation
• Known moderate-to-severe restrictive lung disease (i.e., total lung capacity \< 60% of predicted value) or obstructive lung disease (i.e., forced expiratory volume in one second \[FEV1\] \< 60% of predicted, with FEV1 / forced vital capacity \< 65%) or known significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung disease, emphysema).
• Known or suspected pulmonary veno-occlusive disease (PVOD)
• Severe renal insufficiency (creatinine clearance \< 30 mL/min)
• Documented severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin \> 3 x ULN or serum AST and/or ALT \> 3xULN (assessed by local laboratory at screening) and/or Child-Pugh Class C.
• Haemoglobin \< 10 g/dL
• Patient under guardianship curatorship, deprived of liberty
• Pregnant women, or breast-feeding women
• Treatment with other PDE-5i for erectile dysfunction
• Ongoing or planned treatment with nitrates and/or doxazosin.
• Ongoing or planned treatment with riociguat
• Treatment with strong inducers of CYP3A4 (e.g., carbamazepine, rifampin, rifampicin, rifabutin, rifapentin, phenobarbital, phenytoin, and St. John's wort) ≤28 days preceding randomisation