Comparison of Sequential to Initial Combination Therapy in PAH

Exclusion Criteria34

• \. Other types of pulmonary arterial hypertension (PAH)
• Other types of PAH, such as HIV-related PAH, schistosomiasis-related PAH, etc.
• Pulmonary arterial hypertension associated with portal hypertension
• Pulmonary vein occlusive disease or pulmonary capillary hemangiomatosis 2. Group 4 PH, e.g. Chronic thromboembolic pulmonary hypertension 3. Group 2 PH, i.e., PH associated with left heart disease 4. Group 3 PH, i.e., PH associated with lung disease or hypoxia 5. Group 5 PH, i.e., PH with unclear mechanisms or multi-mechanism 6. PAH Therapy
• \) Subjects who have received PAH therapy (such as PDE5 inhibitors, ERAs, or chronic prostacyclin therapy) within 4 weeks prior to the screening visit.
• \) Subjects who have ever received ERA therapy (e.g., macitentan) or PDE5 inhibitor therapy (e.g., sildenafil) and discontinued due to tolerance issues unrelated to liver dysfunction.
• \) Subjects known to have an allergy to the investigational product, its metabolites, or excipients.
• \. Other Therapies
• Subjects who have received intravenous inotropes (e.g., dobutamine) within 2 weeks prior to the screening visit.
• Subjects receiving protease inhibitors, systemic ketoconazole, or systemic itraconazole therapy.
• Subjects receiving strong CYP3A4 inducers (e.g., rifampicin).
• Subjects who have received unstable doses of calcium channel blockers or HMG-CoA reductase inhibitors (statins) within 4 weeks prior to the screening visit (eligible subjects must not have changed doses within 4 weeks prior to the screening visit).
• Subjects with a history of angina or who have received long-acting or short-acting nitrate treatment within the 12 weeks prior to the visit.
• \. Laboratory Tests at Screening
• ） Serum ALT or AST laboratory values \> 2 times the upper limit of normal at screening.
• ） Serum bilirubin laboratory values \> 1.5 times the upper limit of normal at screening.
• ） Severe renal impairment (estimated glomerular filtration rate \< 45 mL/min/1.73m3) at screening.
• \. Medical History/Current Medical Conditions
• Severe liver dysfunction (Child-Pugh Class C, with or without cirrhosis) at screening.
• Significant anemia in the opinion of the investigator.
• History of bleeding disorders or significant active peptic ulcers.
• Uncontrolled hypertension (≥ 180/110 mmHg) at screening.
• Severe hypotension (\< 90/50 mmHg) at screening.
• Myocardial infarction within 3 months prior to screening.
• Clinically significant aortic or mitral valve disease, constrictive pericarditis, restrictive or congestive cardiomyopathy, life-threatening arrhythmias, significant left ventricular dysfunction, left ventricular outflow tract obstruction, symptomatic coronary artery disease, autonomic hypotension, or circulatory failure.
• History of non-arteritic anterior ischemic optic neuropathy.
• Hereditary degenerative retinal disease (e.g., retinitis pigmentosa).
• Significant fluid retention in the opinion of the investigator.
• Subjects with cardiovascular, liver, kidney, hematologic, gastrointestinal, immune, endocrine, metabolic, or central nervous system diseases that the investigator believes may adversely affect the subject's safety and/or the efficacy of the investigational product or significantly impact the subject's lifespan.
• History of malignant tumors within the past 5 years, except for those with local, non-metastatic basal cell carcinoma, cervical carcinoma in situ, or prostate cancer who are not anticipated to receive radiotherapy, chemotherapy, and/or surgical interventions or initiate hormonal therapy during the study period.
• Pregnant or breastfeeding female subjects.
• Subjects with demonstrated poor compliance.
• History of alcohol abuse or illicit drug use within 1 year.
• Participation in clinical studies involving another investigational drug or device within 4 weeks prior to the screening visit.