Comparison of Sequential to Initial Combination Therapy in PAH

Korábbi kezelés

• 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
• 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).
• Myocardial infarction within 3 months prior to screening.
• 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.
• 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.

Más betegség

• 1\. 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
• History of bleeding disorders or significant active peptic ulcers.
• Uncontrolled hypertension (≥ 180/110 mmHg) at 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).
• 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.
• History of alcohol abuse or illicit drug use within 1 year.

Laborértékek

• 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.
  • 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

Egyéb

• Severe liver dysfunction (Child-Pugh Class C, with or without cirrhosis) at screening.
• Significant anemia in the opinion of the investigator.
• Severe hypotension (\< 90/50 mmHg) at screening.
• Significant fluid retention in the opinion of the investigator.
• Pregnant or breastfeeding female subjects.
• Subjects with demonstrated poor compliance.

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