Trial to Evaluate Parenteral Treprostinil and Riociguat on Right Ventriculo-vascular Coupling and Morphology in Those With Advanced PAH

Inclusion Criteria:

• WHO Category I PAH

• Resting mPAP ≥ 25 mmHg with a wedge pressure of ≤ 15mmHg during right heartcatheterization.

• Need for parenteral TRE as determined by the PH specialist caring for the patient

Exclusion Criteria:

• Patients with a mean arterial pressure <60, and/or requiring vasopressor support

• Patients whom expected device (i.e. ECMO, RVAD) assistance or early pulmonarytransplantation (within 3 months) seems inevitable

• Patients with a left ventricular ejection fraction <50% or clinical,echocardiographic, and/or catheterization data consistent with heart failure withpreserved ejection fraction (HFpEF) and/or moderate-severe aortic or mitral valveabnormality

• Patients with severe restrictive lung disease (FVC<70% predicted) and/or obstructivelung disease (FEV1 <70% predicted and FEV1/FVC <70%).

• Patients with a history of pulmonary embolism within the last three months orevidence of chronic pulmonary embolism.

• Patients with a known contraindication to right heart catheterization.

• Patients whom have received active or previous pulmonary vasoactive medicationwithin the previous 12 weeks.

• PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg),known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis.

• Pulmonary Hypertension belonging to groups 2 to 5 of the WHO classification.

• Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.

• Estimated creatinine clearance < 30 mL/min

• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5times the upper limit of normal.

• Hemoglobin < 75% of the lower limit of the normal range.

• Acute or chronic physical impairment (other than dyspnea), limiting the ability tocomply with study requirements.

• Pregnant or breast-feeding.

• Females must either abstain from intercourse (when it is in line with theirpreferred and usual lifestyle), or

• Use 2 medically acceptable, highly effective forms of contraception for theduration of study, and at least 30 after discontinuing study drug.

• Known concomitant life-threatening disease with a life expectancy < 12 months.

• Body weight < 40 kg and/or >150 kg.

• Any condition that prevents compliance with the protocol or adherence to therapy.

• Concurrent therapy with strong CYP3A4 inhibitors/inducers (i.e. protease inhibitors,azole antibiotics, macrolides), theophylline, and any medication in the PI's opinionmay substantially potentiate the hypotensive effect of RIO.

• Treatment with nitrates of any kind within the 4 weeks prior to enrollment.

• Known hypersensitivity to drugs of the same class as TRE and/or RIO, or any of theirexcipients.

• Planned treatment, or treatment, with another investigational drug within 1 monthprior to randomization.

• Recent (<6 months) hemoptysis and/or history of severe hemoptysis requiringintervention (bronchial artery embolization).