Ambrisentan for Early Low-Risk Pulmonary Arterial Hypertension

Official title

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

Overview

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

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.

Interventions

• 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 (w
• 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.

Primary outcome measures

• The primary efficacy endpoint is the composite of pulmonary hypertension progression at 12 months [Time frame: baseline,12 months]

Secondary outcome measures (12)

• systolic PAP (sPAP) by Hemodynamic measurements [Time frame: baseline,12 months]
• mPAP by Hemodynamic measurements [Time frame: baseline,12 months]
• cardiac output (CO) by Hemodynamic measurements [Time frame: baseline,12 months]
• cardiac index (CI) by Hemodynamic measurements [Time frame: baseline,12 months]
• PVR by Hemodynamic measurements [Time frame: baseline,12 months]
• PVRi by Hemodynamic measurements [Time frame: baseline,12 months]
• PAWP by Hemodynamic measurements [Time frame: baseline,12 months]
• right atrial pressure by Hemodynamic measurements [Time frame: baseline,12 months]
• pulmonary arterial compliance by Hemodynamic measurements [Time frame: baseline,12 months]
• diameter of chambers by Echocardiographic measurements [Time frame: baseline,12 months]
• ejection fraction by Echocardiographic measurements [Time frame: baseline,12 months]
• right ventricular (RV) fraction of area change (FAC) by Echocardiographic measurements [Time frame: baseline,12 months]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Kan JY, Zhang XJ, Yu WD, Yang ZW, Fan FL, Ding GW, Luo J, Li W, Xie DJ, Liu XF, Zhang H, Chen SL. Ambrisentan for Early-Stage Low-Risk Pulmonary Arterial Hypertension: Design of the Randomized, Double-Blind, Placebo-Controlled ALEPH Trial. JACC Asia. 2026 May;6(5):724-732. doi: 10.1016/j.jacasi.2025.12.014. Epub 2026 Feb 7. PMID 41653169

Identifiers

NCT: NCT06987097 · KY20250327-11

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗