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.

This is a multicenter, randomized, controlled, double-blind, and non-inferiority clinical trial to compare the efficacy of sequential to initial combination therapy in symptomatic patients with PAH (WHO functional class I-III) and assessed as low-risk or moderate-risk based on 2022 ESC/ERS risk stratification. Subjects must not have previously received chronic PAH therapy (i.e., prostanoids, ERAs, or PDE-5 inhibitors) within 4 weeks prior to Screening.

Treatment Escalation

1. The investigators will conduct a risk stratification assessment based on COMPERA 2.0 every 4 months, i.e. at month 4, 8, and 12.

2. If the patient meets the low-risk criteria, their current treatment regimen will be maintained, and both the patient and the investigator will be unaware of the specific regimen.

3. If the patient does not meet the low-risk criteria:

1. No clinical failure events have occurred: The first step is to escalate to blinded dual therapy.

   1. The investigator initiates a request for blinded dual therapy, and the pharmacist informs the investigator that the treatment plan has been upgraded as requested.
   2. If the patient is currently on mono therapy, the pharmacist will escalate the regimen to dual therapy.
   3. If the patient is currently in the initial combination therapy group or has already escalated to blinded dual therapy, the pharmacist will maintain the current dual therapy regimen.

2. If any clinical failure event occurs at any time, as determined by the Clinical Event Evaluation Committee:

   1. Escalate to blinded dual therapy as described above
   2. Or add prostacyclin analogue
   3. Or add IP receptor agonist
   4. Or transition of Tadalafil to Riociguat
   5. Or add Sotatercept

Primary efficacy endpoint is exercise capacity, as the change in 6MWD at month 12 from baseline. Secondary efficacy endpoints will include time to clinical failure events during the 12-month treatment period, and others detailed in outcome measures.

Study duration will be approximately 4 years. A non-inferiority test will be conducted based on the mean difference and 95% CI of the change in 6MWD between groups after 12 months of treatment following randomization. An unblinded, external, independent DSMB will monitor participants' data and safety throughout the course of the study.

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:

1. Connective tissue diseases (e.g., scleroderma, systemic lupus erythematosus, mixed connective tissue disease, etc.)

2. Drug or toxin exposure

3. 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.

   5. 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.

   6. 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.