Comparison of Sequential to Initial Combination Therapy in PAH

NCT06968962 | Recruiting DMC

• 1 other identifier: YAN2024-1201
• Study Type: interventional
• Target: 376
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Pulmonary Arterial Hypertension (PAH)

Keywords

Sequential combination therapy; Initial combination therapy; Pulmonary Arterial Hypertension

Outcome Measures

Primary Outcomes (1)

• The change of 6MWD at month 12 from baseline

  The 6MWD was the distance walked in 6 minutes as a measure of functional capacity. This was assessed using the 6-minute walk test (6MWT).

  Baseline and Month 12

Secondary Outcomes (8)

• Time to clinical failure events during the 12-month treatment period.

  During the 12-month treatment period

• Low-risk status achievement rates.

  Month 4, 8 and 12

• The change of NT-proBNP at month 12 from baseline

  Baseline and Month 12

• The change of WHO functional class at month 12 from baseline

  Baseline and Month 12

• The change of pulmonary vascular resistance at month 12 from baseline

  Baseline and Month 12

Study Arms (3)

Initial combination therapy

ACTIVE COMPARATOR

Patients will receive dual combination therapy with Ambrisentan and Tadalafil immediately after randomization.

Drug: Tadalafil; Drug: Ambrisentan

Sequential combination therapy (B1 group)

EXPERIMENTAL

Patients will receive Ambrisentan and Tadalafil mimic first, with sequential addition of Tadalafil if low risk status was not achived at month 4, or 8, or 12.

Drug: Ambrisentan; Drug: Tadalafil mimic

Sequential combination therapy (B2 group)

EXPERIMENTAL

Patients will receive Tadalafil and Ambrisentan mimic first, with sequential addition of Ambrisentan if low risk status was not achived at month 4, or 8, or 12.

Drug: Tadalafil; Drug: Ambrisentan mimic

Interventions

Tadalafil DRUG

Target dose 40 mg OD

Initial combination therapy; Sequential combination therapy (B2 group)

Ambrisentan DRUG

Target dose 10 mg OD

Initial combination therapy; Sequential combination therapy (B1 group)

Ambrisentan mimic DRUG

Ambrisentan mimic will switch to Ambrisentan if low risk status was not achived at month 4, or 8, or 12.

Sequential combination therapy (B2 group)

Tadalafil mimic DRUG

Tadalafil mimic will switch to Tadalafil if low risk status was not achived at month 4, or 8, or 12.

Sequential combination therapy (B1 group)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age between 18 to 80 years and weight ≥ 40 kg.
• WHO functional classification I-III.
• Diagnosed with PAH caused or related to the following:
• \) 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.
• \. Right heart catheterization meets the following criteria (end-expiratory data, original waveform must be retained for quality control):
• \) 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.
• \. Pulmonary function tests meet the following criteria:
• ） 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%.
• \. No participation in cardiopulmonary rehabilitation training programs within 12 weeks prior to the screening visit.
• \. Females of childbearing potential must agree to use contraception until the end of the study.
• \. No participation in clinical studies involving other investigational drugs or devices throughout the study duration.
• \. Ability to understand the informed consent form and sign it.

You may not qualify if:

• \. 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.

Sponsors & Collaborators

• Second Affiliated Hospital, School of Medicine, Zhejiang University: lead
• Huzhou Central Hospital: collaborator
• Ningbo Medical Center Lihuili Hospital: collaborator
• First Affiliated Hospital of Ningbo University: collaborator
• Ningbo No.2 Hospital: collaborator
• Affiliated Hospital of Jiaxing University: collaborator
• The Second Affiliated Hospital of Jiaxing University: collaborator
• First Affiliated Hospital of Wenzhou Medical University: collaborator
• Shanghai Pulmonary Hospital affiliated to Tongji University: collaborator
• Taizhou Hospital: collaborator
• Guangdong Provincial People's Hospital: collaborator

Study Sites (1)

The Second Affiliated Hospital, Zhejiang University School of Medicine

Hangzhou, Zhejiang, 310058, China

RECRUITING

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

Tadalafil; ambrisentan

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Central Study Contacts

Zongye Cai, MD, PhD

CONTACT

+8618258236820; z.cai@zju.edu.cn

Zexin Chen

CONTACT

+86 15867136069; chenzexin@zju.edu.cn

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: April 20, 2025
• First Posted: May 13, 2025
• Study Start: May 14, 2025
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: July 29, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)