The purpose of this study is to determine if there is a greater effect to patients with advanced pulmonary arterial hypertension (PAH) by using a combination of two drugs, Treprostinil and Riociquat versus Treprostinil alone

The purpose of this study is to evaluate the combined effect of parenteral treprostinil (TRE) and riociguat (RIO) versus parenteral TRE alone on right ventricular (RV)-pulmonary artery (PA) interaction (RVPA coupling) and global RV function in patients with advanced pulmonary arterial hypertension (PAH).

Inclusion Criteria:

• WHO Category I PAH
• Resting mPAP ≥ 25 mmHg with a wedge pressure of ≤ 15mmHg during right heart catheterization.
• 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 pulmonary transplantation (within 3 months) seems inevitable

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

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

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

• Patients with a known contraindication to right heart catheterization.

• Patients whom have received active or previous pulmonary vasoactive medication within 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) > 1.5 times 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 to comply with study requirements.

• Pregnant or breast-feeding.

  • Females must either abstain from intercourse (when it is in line with their preferred and usual lifestyle), or
  • Use 2 medically acceptable, highly effective forms of contraception for the duration 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 opinion may 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 their excipients.

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

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