Ambrisentan for Early Low-Risk Pulmonary Arterial Hypertension (ALEPH)

Ambrisentan for the Treatment of Early-Stage Low-Risk Pulmonary Arterial Hypertension: A Multicenter, Randomized, Double-Blind, Placebo-Controlled ALEPH Trial

This is an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical trial.

Study Overview

• Status: Not yet recruiting
• Conditions: Pulmonary Arterial Hypertension (PAH)
• Intervention / Treatment: Drug: Ambrisentan; Drug: Placebo

Detailed Description

Early-stage low-risk PAH is defined as mean pulmonary arterial pressure (mPAP) between 20 and 25 mmHg at rest, measured by right heart catheterization, and classified as low-risk based on the 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Patients will be randomized at a 1:1 ratio to either the treatment group (Ambrisentan group) or the control group (Placebo group). Treatment group: Ambrisentan, with an initial dose of 5 mg/day (one tablet per day).Control group: Placebo, which will be provided in the same appearance and taste as Ambrisentan, one tablet per day.

After two weeks of initial treatment, the study drugs' dose will be increased to two tablets per day (10 mg/day). If the patient cannot tolerate the increased dose (e.g., experiencing headache, dizziness, palpitations, hypotension, or other drug-related symptoms or signs), the dose will be reduced to 5 mg/day. If the study drug has reached the maximum allowable dose (two tablets/day) and the patient shows signs of worsening PAH or right heart failure, the clinician may decide to add diuretics (with the type and dosage left at the referring physician's discretion). The number and percentage of patients requiring diuretic combination therapy in both groups will be recorded. Other baseline treatment medications will remain unchanged through follow-up duration.

The study drugs will be administered continuously for 12 months, then unblinding will be performed. Thereafter, patients who have reached the primary endpoint must undertake Ambrisentan. For patients who have not reached the primary endpoint, the subsequent medications treatment will be left at the PAH specialist's discretion. Follow-up will be undertaken at the following timing: Month 1, Month 6, and Month 12, with additional follow-up extending up to 3 years. All clinical drugs involved in this study have completed registration for market approval in China and are currently in clinical use.

• Study Type: Interventional
• Enrollment (Estimated): 410
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Han Zhang MD, PhD; Phone Number: +86-25-52271330; Email: dxh_nari@sina.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years;
• mPAP > 20 mmHg and < 25 mmHg, pulmonary vascular resistance (PVR) > 2 WUs and ≤ 3 WUs, and pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg via right heart catheterization (RHC); RHC measurement will be accepted if it was done within 7 days before enrollment;
• Group I PAH, including idiopathic PAH (IPAH), heritable PAH (HPAH), Drug- and toxin-induced PAH, associated with connective tissue disease (connective tissue disease at good control), associated with portal hypertension, associated with congenital heart disease;
• At low risk based on the 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension three-strata risk-assessment model;
• The subject or a legally authorized representative must understand the study requirements, agree to the treatment procedures, and provide written informed consent before any study-specific procedures are performed;
• The subject must demonstrate a willingness and ability to comply with all protocol requirements.

Exclusion Criteria:

• Patients currently receiving PAH specific medications, regardless of whether mPAP is between 20-25 mmHg. PAH specific medications include endothelin receptor antagonists (ERAs; e.g., bosentan, ambrisentan, macitentan), phosphodiesterase type 5 inhibitors (PDE5i; e.g., sildenafil, tadalafil, vardenafil), prostacyclin analogs (e.g., iloprost, epoprostenol, treprostinil, beraprost), soluble guanylate cyclase stimulators (e.g., riociguat). Intermittent use of PDE5 inhibitors for the treatment of male erectile dysfunction is permitted;
• Intolerance to ambrisentan or its excipients;
• Pulmonary veno-occlusive disease (PVOD);
• Pulmonary capillary hemangiomatosis (PCH);
• Within 6 months after congenital heart disease surgical repair or percutaneous closure procedure;
• Group II-V PH;
• Clinically significant anemia, defined as hemoglobin concentration below 75% of the lower limit of normal;
• Renal insufficiency, defined as estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m² within 3 months prior to enrollment;
• Elevated Alanine Aminotransferase （ALT） and/or Aspartate Aminotransferase （AST） exceeding 3 times the upper limit of normal (ULN);
• Systolic blood pressure < 85 mmHg;
• Uncontrolled hypertension, defined as blood pressure > 160/90 mmHg at rest and/or > 220/120 mmHg under stress conditions;
• Participation in any clinical drug trial within 4 weeks prior to screening and/or planned participation in another clinical drug trial during this study;
• Expected life expectancy of less than 1 year;
• Pregnant or breastfeeding women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ambrisentan; Monotherapy using ambrisentan will start at a dose of 5 mg (once daily) and will be up-titrated to 10mg (once daily) after 2 weeks apart if patients are tolerable.	Drug: Ambrisentan; After two weeks of initial treatment, the study drugs' dose will be increased to two tablets per day (10 mg/day). If the patient cannot tolerate the increased dose (e.g., experiencing headache, dizziness, palpitations, hypotension, or other drug-related symptoms or signs), the dose will be reduced to 5 mg/day. If the study drug has reached the maximum allowable dose (two tablets/day) and the patient shows signs of worsening PAH or right heart failure, the clinician may decide to add diuretics (with the type and dosage left at the referring physician's discretion). The number and percentage of patients requiring diuretic combination therapy in both groups will be recorded. Other baseline treatment medications will remain unchanged through follow-up duration.
Placebo Comparator: Placebo Placebo tablet; Placebo tablet (one to two tablets corresponding to one to two verum tablets).	Drug: Placebo; Placebo tablet (one to two tablets corresponding to one to two verum tablets). Administration: Placebo will be administrated orally with or without food intake in the morning.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary efficacy endpoint is the composite of pulmonary hypertension progression at 12 months	defined as meeting any of the following criteria within 12 months: mPAP ≥ 25 mmHg OR PVR > 3 WUs as measured by RHC OR; worsening of risk stratification compared to baseline, defining as at least one class progression based on the simplified four-tier model of the 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension	baseline,12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
systolic PAP (sPAP) by Hemodynamic measurements		baseline,12 months
mPAP by Hemodynamic measurements		baseline,12 months
cardiac output (CO) by Hemodynamic measurements		baseline,12 months
cardiac index (CI) by Hemodynamic measurements		baseline,12 months
PVR by Hemodynamic measurements		baseline,12 months
PVRi by Hemodynamic measurements		baseline,12 months
PAWP by Hemodynamic measurements		baseline,12 months
right atrial pressure by Hemodynamic measurements		baseline,12 months
pulmonary arterial compliance by Hemodynamic measurements		baseline,12 months
diameter of chambers by Echocardiographic measurements		baseline,12 months
ejection fraction by Echocardiographic measurements		baseline,12 months
right ventricular (RV) fraction of area change (FAC) by Echocardiographic measurements		baseline,12 months
TAPSE by Echocardiographic measurements		baseline,12 months
pulmonary artery accelation time (PAAT) by Echocardiographic measurements		baseline,12 months
regurgitation of tricuspid or pulmonary valve by Echocardiographic measurements		baseline,12 months
sPAP by Echocardiographic measurements		baseline,12 months
RAP by Echocardiographic measurements		baseline,12 months
WHO functional class through follow - up		baseline,12 months
Borg index through follow - up		baseline,12 months
N-terminal-pro BNP		baseline,12 months
6-minute walk distance (6MWD)		baseline,12 months
Time to the first occurrence of the following events, analyzed using log-rank and LWYY model	All-cause mortality; Hospitalization due to PAH worsening; Clinical deterioration of PAH, defined as the need for diuretics or digoxin (oral or intravenous), or the need of combination therapy with PAH specific medications; 6MWD decreases by 10% or 30m	baseline,12 months

Collaborators and Investigators

• Sponsor: Nanjing First Hospital, Nanjing Medical University
• Investigators: Study Chair: Shao-Liang Chen MD, PhD, Nanjing First Hospital, Nanjing Medical University

Study record dates

Study Major Dates

• Study Start (Estimated): May 15, 2025
• Primary Completion (Estimated): February 28, 2028
• Study Completion (Estimated): March 1, 2029

Study Registration Dates

• First Submitted: April 24, 2025
• First Submitted That Met QC Criteria: May 15, 2025
• First Posted (Actual): May 23, 2025

Study Record Updates

• Last Update Posted (Actual): May 23, 2025
• Last Update Submitted That Met QC Criteria: May 15, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Hypertension; Familial Primary Pulmonary Hypertension; Antihypertensive Agents; Ambrisentan
• Other Study ID Numbers: KY20250327-11

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No