Sequential versus initial combination treatment for pulmonary arterial hypertension

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

This trial tests whether starting with one drug and adding the second later works as well as starting both ambrisentan and tadalafil together for adults with PAH.

Quick facts

• Phase: NA
• Study type: Interventional
• Enrollment: 376 (estimated)
• Ages: 18 Years to 80 Years
• Sex: All
• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University (other)
• Drugs / interventions: chemotherapy
• Locations: 1 site (Hangzhou, Zhejiang)
• Trial ID: NCT06968962 on ClinicalTrials.gov

What this trial studies

This multicenter, randomized, double-blind non-inferiority trial compares sequential versus initial combination therapy using ambrisentan and tadalafil in adults with PAH. Participants are WHO functional class I–III, judged low- or intermediate-risk by 2022 ESC/ERS criteria, must have right heart catheterization–confirmed PAH, and must not have recent chronic PAH therapy. The primary endpoint is change in 6-minute walk distance at 12 months, with risk re-stratification every 4 months using COMPERA 2.0 and blinded escalation to dual therapy if patients do not meet low-risk criteria. Placebo/mimic tablets are used so patients, investigators, and pharmacists manage blinded escalation without revealing the original assignment.

Who should consider this trial

Good fit: Adults aged 18–80 years weighing ≥40 kg with idiopathic, heritable, or certain associated PAH (WHO FC I–III), low- or intermediate-risk by 2022 ESC/ERS criteria, and right heart catheterization meeting hemodynamic thresholds are ideal candidates.

Not a fit: Patients with high-risk or WHO FC IV PAH, recent prostanoid or chronic PAH therapy use, or those who cannot meet the hemodynamic or age/weight criteria are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, it could allow many patients to start with one medication and add a second only when needed, minimizing unnecessary drug exposure and side effects while maintaining exercise capacity.

How similar studies have performed: Prior trials such as AMBITION showed benefit of initial ambrisentan plus tadalafil over monotherapy, but direct randomized non-inferiority comparisons of sequential versus upfront combination therapy are limited, making this partially novel.

Eligibility criteria

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.

Where this trial is running

Hangzhou, Zhejiang

• The Second Affiliated Hospital, Zhejiang University School of Medicine — Hangzhou, Zhejiang, China (RECRUITING)

Study contacts

• Study coordinator: Zongye Cai, MD, PhD

Conditions: Pulmonary Arterial Hypertension, Sequential combination therapy, Initial combination therapy