Treatment With Ambrisentan in Patients With Borderline Pulmonary Arterial Hypertension (TAPE)

Treatment With Ambrisentan in Patients With Borderline Pulmonary Arterial Hypertension: a Multicenter, Randomized, Double-blind, Placebo-controlled Study

An Investigator initiated trial (IIT) using a prospective, randomized, double-blind, parallel group, placebo-controlled, clinical study design.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Ambrisentan; Drug: Placebo

Detailed Description

The treatment options and prognosis of patients with borderline pulmonary arterial hypertension (PAH) defined as mean pulmonary arterial pressure (mPAP) between 21-24 mm Hg measured by right heart catheterization (RHC) are understudied. The objective of this study is to determine the treatment effect of endothelin-receptor antagonist (Ambrisentan) for patients with borderline PAH when comparing with placebo. Accordingly, 420 patients with borderline PAH will be included in this prospective, randomized, double- blind, parallel group, placebo-controlled study. Repeat screening is required if last screening was performed > 30 days ago. Baseline medical history will be obtained and physical examination will be conducted before signed consent and randomization. Moreover, an electrocardiogram (ECG), laboratory testing, and transthoracic echocardiography (TTE) at supine will be carried out before randomization and during follow-up. Subjects have to meet all inclusion criteria and have no anyone of exclusion criteria. This study will comprise 3 stages: 1) screening period (0-30 days), 2) 1-year study period (365 ± 30 days), 3) extended follow-up duration 3 years ± 30 days. Repeat measurements of cardiac function, hemodynamic, exercise capacity, and clinical events will be scheduled at the end of study.

• Study Type: Interventional
• Enrollment (Anticipated): 420
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Zhen-Wen Yang, MD, PhD; Phone Number: +86-13920889629; Email: yzwmd@hotmail.com
• Study Contact Backup: Name: Han Zhang, MD, PhD; Phone Number: +86-25-52271330; Email: dxh_nari@sina.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210006
      • Recruiting
      • Nanjing First Hospital
      • Contact: Shao-Liang Chen, PHD; Phone Number: 02552271350; Email: chmengx@126.com
      • Contact: Hang Zhang, PHD; Phone Number: 02552271330; Email: dxh_nari@sina.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject must be age ≥18 years;
• Subject has mPAP 21-24 mmHg, and PAWP<15mmHg.The underlying diseases that cause critical PAH belong to the first group, which is divided into: Idiopathic pulmonary hypertension, hereditary pulmonary hypertension, drugs and poisons associated with pulmonary hypertension, connective tissue diseases associated with pulmonary hypertension, HIV infection associated with pulmonary hypertension, portal hypertension associated with pulmonary hypertension, tumors associated with pulmonary hypertension, congenital heart disease associated with pulmonary hypertension.
• Subject (or legal guardian) understands the trial design and treatment procedures and provides written informal consent before any trial-specific tests or procedures are performed.

Exclusion Criteria:

• Pulmonary hypertension (PH) confirmed by right heart catheter (RHC) before enrolment, i.e. mPAP ≥25 mmHg at rest.
• Ongoing or a history of >2 weeks of continued use of therapies that are considered definitive PH treatment: endothelin receptor antagonists (ERA; e.g. bosentan, ambrisentan), phosphodiesterase type 5 inhibitors (PDE5; e.g. sildenafil, tadalafil, vardenafil), prostanoids (e.g. epoprostenol, treprostinil, iloprost, beraprost) and soluble guanylate cyclase stimulator (e.g. Riociguat). Intermittent use of PDE5 inhibitors for male erectile dysfunction is permitted.
• Known intolerance to ambrisentan or one of its excipients.
• Pulmonary vein occlusive disease
• Pulmonary capillary hemangiomatosis
• Surgical repair or interventional occlusion of congenital heart disease within 6 months prior to screening of this study
• Active connective tissue diseases
• Pulmonary hypertension due to left heart disease
• Pulmonary hypertension due to pulmonary disease and/or hypoxia
• Acute pulmonary embolism and/or chronic thromboembolism
• Clinically significant anemia, defined as hemoglobin concentration 75% below the normal lower limit.
• Renal insufficiency was defined as glomerular filtration rate [EGFR] <30 mL/min/1.73m2.
• Transaminase (ALT and/or AST) increased, exceeding the upper limit of normal value by 3 times.
• Arterial systolic blood pressure < 85 mmHg.
• Uncontrolled hypertension, defined as blood pressure >160/90 mmHg (resting state) and/or >220/120 mmHg (load state).
• Participate in any drug clinical trial within 4 weeks prior to screening in this study and/or plan to participate in another drug clinical trial during the study period.
• Pregnant or lactating 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
Placebo Comparator: Placebo; Placebo tablet	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.
Experimental: Ambrisentan; Monotherapy using ambrisentan will start at a dose of 5 mg (once daily) and will be up-titrated to 10 mg (once daily) after 4 weeks apart if patients are tolerable.	Drug: Ambrisentan; Titration: Monotherapy using ambrisentan will be initialized at a beginning dose of 5 mg (once daily). Drug intake is scheduled at the morning. After 4 weeks monitoring, the dose of ambrisentan will be uptitrated to 10 mg once daily. Otherwise, if intolerability is indicated, a dose of 5 mg (once daily) will be maintained through the study duration. Maximum dose allowed: not to exceed 10 mg/day. Administration: Ambrisentan will be administered orally with or without food intake.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of diagnostic PAH (mPAP ≥25 mmHg)	Determine whether mean pulmonary arterial pressure of patients with borderline - PAH (mPAP 21-24 mmHg) can be reduced by 3 mm Hg (absolute change baseline vs. 1 year; equals 15%) following treatment with ambrisentan 10 mg/die (initiated with 5 mg/die and elevated up to 10 mg/die) over 1 year (primary endpoint) compared to baseline and placebo.	baseline, 1 year
Change of Pulmonary vascular resistance	Pulmonary vascular resistance by right heart catheterization	baseline, 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Re-hospitalization due to clinical worsening	Re-hospitalization is defined as clinical manifestations of worsening PAH requiring re-hospitalization in order to add intravenous pharmacological agents (inotrope or vasodilator), mechanical intervention or ultrafiltration, hemofiltration, or dialysis.	baseline, 3 years
All-cause mortality		baseline, 3 years
6-Minute-walking Test		baseline, 1 year
Right atrial pressure by right heart catheterization		baseline, 1 year
Cardiac output (CO) by right heart catheterization		baseline, 1 year
Cardiac index (CI) by right heart catheterization		baseline, 1 year
RA-area (right atrial area) by echocardiography		baseline, 1 year
RV-area (right ventricular area) by echocardiography		baseline, 1 year
Tei by echocardiography	Tei	baseline, 1 year
TAPSE (tricuspid annular plane systolic excursion) by echocardiography		baseline, 1 year
sPAP (systolic pulmonary arterial pressure) by echocardiography		baseline, 1 year

Collaborators and Investigators

• Sponsor: Nanjing First Hospital, Nanjing Medical University
• Collaborators: Tianjin Medical University General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2022
• Primary Completion (Anticipated): December 30, 2025
• Study Completion (Anticipated): March 30, 2026

Study Registration Dates

• First Submitted: July 9, 2021
• First Submitted That Met QC Criteria: July 13, 2021
• First Posted (Actual): July 22, 2021

Study Record Updates

• Last Update Posted (Actual): September 28, 2022
• Last Update Submitted That Met QC Criteria: September 27, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Antihypertensive Agents; Ambrisentan
• Other Study ID Numbers: CSC20210527

Drug and device information, study documents

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