Initial Triple Therapy Including Parenteral Treprostinil vs Initial Double Oral Therapy in PAH Group I Patients

TripleTRE investigates the effect of initial triple combination therapy (oral endothelin receptor antagonist (ERA) + oral phosphodiesterase tyüe-5 inhibitor (PDE-5i) + parenteral treprostinil) compared to double oral therapy (oral ERA + oral PDE-5i) in pulmonary arterial hypertension (PAH) patients (group I) with intermediate-high risk or patients with intermediate-low risk with severe hemodynamic impairment at baseline in a prospective, randomized, unblinded setting with scope of increasing evidence for optimization of therapy concepts in PAH. The effect of initial triple combination therapy vs initial double oral therapy (standard of care (SoC)) will be measured by primary endpoint: (non)response to the assigned treatment.

Inclusion Criteria: 1. Signed informed consent prior to any trial-mandated procedure 2. Male or female ≥ 18 and ≤ 75 years of age 3. Newly diagnosed treatment-naïve PAH patients (PH group I) defined as receiving no specific therapy to treat PAH 4. Intermediate-high risk patients or intermediate-low risk with severe haemodynamic impairment fulfilling at least one of the following criteria: CI \< 2.0 L/min, SVI \< 31 mL/m², PVR ≥ 10 WU or SvO2 \< 60 %; rated according to the simplified four-strata risk-assessment tool 5. Right Heart Catheterization (RHC) meeting all the following criteria: * Mean pulmonary arterial pressure (mPAP) \> 20 mmHg * Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg * PVR \> 2 Wood Units 6. Women of childbearing potential must not be pregnant or lactating, must perform regular pregnancy tests, if sexually active, agrees to continue to use reliable method(s) of contraception until study completion Exclusion Criteria: Inclusion criteria at randomization: 1. Signed informed consent prior to any trial-mandated procedure 2. Male or female ≥ 18 and ≤ 75 years of age 3. Newly diagnosed treatment-naïve PAH patients (PH group I) defined as receiving no specific therapy to treat PAH 4. Intermediate-high risk patients or intermediate-low risk with severe haemodynamic impairment fulfilling at least one of the following criteria: CI \< 2.0 L/min, SVI \< 31 mL/m², PVR ≥ 10 WU or SvO2 \< 60 %; rated according to the simplified four-strata risk-assessment tool 5. Right Heart Catheterization (RHC) meeting all the following criteria: * Mean pulmonary arterial pressure (mPAP) \> 20 mmHg * Pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg * PVR \> 2 Wood Units 6. Women of childbearing potential must not be pregnant or lactating, must perform regular pregnancy tests, and agree to continue to use a highly effective birth control method until study completion Exclusion criteria at randomization: 1. PAH patients (PH Group I) belonging to one of the following subgroups: * Schistosomiasis * HIV infection * Portal hypertension * Diffuse systemic sclerosis with organ involvement that, in the opinion of the investigator, may adversely affect the safety of the patient and /or efficacy of the therapy * Uncorrected congenital heart disease including uncorrected systemic-to-pulmonary shunts 2. Patients not able to walk due to concomitant disease 3. Patients responding to vasoreactivity testing with calcium channel blockers (CCB) 4. Post-capillary PH and left heart disease 5. Known or suspected pulmonary veno-occlusive disease (PVOD) 6. Any PH due to lung disease 7. Any disorder of the respiratory system or suspicion of PVOD expressed by DLCO \ 40 (kg/m2) 9. History of restrictive, constrictive or congestive cardiomyopathy, atrial septostomy, any symptomatic coronary disease events within 6 months, severe uncontrolled arterial hypertension, acutely decompensated heart failure and myocardial infarction within 90 days, significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease, chronic systemic hypotension, unstable angina pectoris, permanent/persistent atrial fibrillation and/or need for pacemaker 10. Patients with acute anaemia with haemoglobin (Hb) values \