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

Prior treatment

• Patients not able to walk due to concomitant disease
• Patients with major surgery in the last 12 months that, in the opinion of the investigator, may adversely affect the safety of the patient and /or efficacy of the therapy
• Treatment of a CYP2C8 enzyme inducer (e.g., rifampicin) ≤ 28 days and/or treatment of a cytochrome P450 (CYP)2C8 enzyme inhibitor (e.g., gemfibrozil) ≤ 28 days
• Treatment with another investigational drug (planned, or taken ≤ 12 weeks)

Other illness

• 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
• Post-capillary PH and left heart disease
• Known or suspected pulmonary veno-occlusive disease (PVOD)
• Any PH due to lung disease
• Any disorder of the respiratory system or suspicion of PVOD expressed by DLCO \<40% and a noticeable imaging result (i.e. chest CT, CT pulmonary angiography) and plethysmography or forced spirometry below lower limit of normal
• 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
• Patient with other cardiovascular, liver, renal, haematologic, gastrointestinal (including active gastrointestinal ulcer), immunologic, endocrine (e.g., uncontrolled diabetes), metabolic, or central nervous system disease and acute bleeding and injuries (e.g., intracranial haemorrhage) that, in the opinion of the investigator, may adversely affect the safety of the patient and /or efficacy of the therapy or significantly limit the lifespan (\< 12 months)
• Hypersensitivity to any of the trial treatments or any excipient of their formulations
• Any other significant disease or disorder which, in the opinion of the investigator, may put the patients at risk when participating in the trial
• Any factor or condition likely to affect protocol compliance of the patient, as judged by the investigator

Lab values

• Patients responding to vasoreactivity testing with calcium channel blockers (CCB)
• Patients with acute anaemia with haemoglobin (Hb) values \<11 g/dL
• 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) or by aspartate aminotransferase (AST) ≥5x ULN or alkaline phosphatase ≥5x ULN or Child-Pugh Class C
• Documented renal insufficiency with GFR \<30 ml/min

Other

• Body mass index (BMI) \> 40 (kg/m2)
• Cerebrovascular accident within 3 months
• Patients with untreated sleep apnoea
• Pregnancy, breastfeeding, or intention to become pregnant during the trial

• Signed informed consent prior to any trial-mandated procedure
• Male or female ≥ 18 and ≤ 75 years of age
• Newly diagnosed treatment-naïve PAH patients (PH group I) defined as receiving no specific therapy to treat PAH
• 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
• 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
• 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
• Signed informed consent prior to any trial-mandated procedure
• Male or female ≥ 18 and ≤ 75 years of age
• Newly diagnosed treatment-naïve PAH patients (PH group I) defined as receiving no specific therapy to treat PAH
• 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
• 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
• 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