Overview

This is a multicenter, randomized, controlled, double-blind, and non-inferiority clinical trial to compare the efficacy of sequential to initial combination therapy in patients with pulmonary arterial hypertension (PAH). Ambrisentan and Tadalafil will be used in the study. Our research hypothesis is that the efficacy of sequential combination therapy in PAH patients is not inferior to the initial combination therapy as the primary efficacy endpoint is the change in 6MWD at month 12 from baseline.

Eligibility

Inclusion Criteria:

1. Age between 18 to 80 years and weight ≥ 40 kg.
2. WHO functional classification I-III.
3. Diagnosed with PAH caused or related to the following:
   1. Idiopathic PAH 2) Hereditary PAH 3) Associated PAH:
4. Connective tissue diseases (e.g., scleroderma, systemic lupus erythematosus, mixed

   connective tissue disease, etc.)

5. Drug or toxin exposure
6. Corrected congenital heart diseases for more than 1 year (e.g., atrial septal defect, ventricular septal defect, and patent ductus arteriosus) 4. Risk stratification assessed as low-risk or intermediate-risk according to the 2022 ESC/ERS guidelines.
7. Right heart catheterization meets the following criteria (end-expiratory data,

   original waveform must be retained for quality control):

   1. Mean pulmonary artery pressure ≥ 25 mmHg 2) Pulmonary vascular resistance ≥ 3 Wood units 3) Pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg 4) Cardiac output measurement requirements: thermal dilution or direct Fick method; indirect Fick method does not meet study criteria.
   2. Pulmonary function tests meet the following criteria:

     1） Total lung capacity (TLC) ≥ 60% of the predicted normal value; 2） Forced
     expiratory volume in the first second (FEV1) ≥ 55% of the predicted normal value; 3）
     DLCO_SB ≥ 40% of the predicted normal value. 7. Baseline 6MWD more than 100 meters
     repeated twice at screening (measured at least 4 hours apart, but no longer than 1
     week), and both values are within 15% of each other (calculated from the highest
     value) 8. In a resting state, without supplemental oxygen, arterial oxygen
     saturation (SaO2) ≥ 88%.
       9. No participation in cardiopulmonary rehabilitation training programs within 12
          weeks prior to the screening visit.
      10. Females of childbearing potential must agree to use contraception until the end
          of the study.
      11. No participation in clinical studies involving other investigational drugs or
          devices throughout the study duration.
      12. Ability to understand the informed consent form and sign it.
     Exclusion Criteria:
       1. Other types of pulmonary arterial hypertension (PAH)
       1. Other types of PAH, such as HIV-related PAH, schistosomiasis-related PAH, etc.
       2. Pulmonary arterial hypertension associated with portal hypertension
       3. 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
       1) Subjects who have received PAH therapy (such as PDE5 inhibitors, ERAs, or
          chronic prostacyclin therapy) within 4 weeks prior to the screening visit.
       2) 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.
       3) Subjects known to have an allergy to the investigational product, its
          metabolites, or excipients.
       7. Other Therapies
       1. Subjects who have received intravenous inotropes (e.g., dobutamine) within 2
          weeks prior to the screening visit.
       2. Subjects receiving protease inhibitors, systemic ketoconazole, or systemic
          itraconazole therapy.
       3. Subjects receiving strong CYP3A4 inducers (e.g., rifampicin).
       4. 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).
       5. 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.
       8. Laboratory Tests at Screening
     1） Serum ALT or AST laboratory values > 2 times the upper limit of normal at
     screening.
     2） Serum bilirubin laboratory values > 1.5 times the upper limit of normal at
     screening.
     3） Severe renal impairment (estimated glomerular filtration rate < 45 mL/min/1.73m3)
     at screening.
       9. Medical History/Current Medical Conditions
       1. Severe liver dysfunction (Child-Pugh Class C, with or without cirrhosis) at
          screening.
       2. Significant anemia in the opinion of the investigator.
       3. History of bleeding disorders or significant active peptic ulcers.
       4. Uncontrolled hypertension (≥ 180/110 mmHg) at screening.
       5. Severe hypotension (< 90/50 mmHg) at screening.
       6. Myocardial infarction within 3 months prior to screening.
       7. 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.
       8. History of non-arteritic anterior ischemic optic neuropathy.
       9. Hereditary degenerative retinal disease (e.g., retinitis pigmentosa).
      10. Significant fluid retention in the opinion of the investigator.
      11. 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.
      12. 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.
      13. Pregnant or breastfeeding female subjects.
      14. Subjects with demonstrated poor compliance.
      15. History of alcohol abuse or illicit drug use within 1 year.
      16. Participation in clinical studies involving another investigational drug or
          device within 4 weeks prior to the screening visit.
     Subjects who fail inclusion/exclusion criteria may be re-screened once.