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Efficacy and Safety Study of Ambrisentan in Chinese Patients With Pulmonary Arterial Hypertension (AMBLE)

Primary Purpose

Pulmonary Arterial Hypertension

Status
Completed
Phase
Phase 3
Locations
China
Study Type
Interventional
Intervention
Ambrisentan
Sponsored by
RenJi Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Arterial Hypertension focused on measuring PAH, ambrisentan

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age ≥18 years old and ≤75 years old, regardless of gender;
  • patients weighing ≥ 40 kg;
  • Patients diagnosed with PAH in Group 1 of the WHO Updated Clinical Classification of Pulmonary Hypertension (WHO functional class II or III);
  • 6 min walk test (6MWT), walking distance ≥ 50 m;

  • Right heart catheterization performed within 6 months prior to screening and meeting the following hemodynamic criteria:

    1. mean pulmonary artery pressure ≥ 25 mm Hg；
    2. Pulmonary vascular resistance ≥ 240 dyn·s·cm-5;
    3. Pulmonary artery wedge pressure or left ventricular end-diastolic pressure ≤ 15 mmHg;
  • Subject receiving calcium channel blocker (CCB) drugs, only those whose doses have been stabilized for more than 4 weeks at the time of screening are allowed to be included in the study;

  • Pulmonary function testing performed within 6 months prior to screening and meeting the following criteria：

    1. Total lung capacity ≥ 60% of normal predicted value;
    2. Forced expiratory volume in one second (FEV1) ≥ 55% of normal expected value;
  • Female subjects of childbearing potential must have a negative pregnancy test at the Screening Visit and Day 0;
  • Females subjects of childbearing potential must use a medically acceptable method of contraception (eg, hormone therapy, IUD, barrier methods such as condoms or cervical caps) during the study;
  • Sign written informed consent

Exclusion Criteria:

  • Patients diagnosed with WHO updated PH clinical classification of group 2, 3, 4, 5;
  • Endothelin receptor antagonist therapy (eg, bosentan) has been discontinued prior to enrollment due to safety or tolerability concerns (non-drug-induced liver function abnormalities);
  • Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 2 times ULN;
  • Serum bilirubin level > 1.5 times ULN;
  • severe hepatic insufficiency (Child-Pugh class C);
  • severe renal insufficiency (creatinine clearance <30 mL/min);
  • Hemoglobin concentration < 10 g/dL or hematocrit < 30%;
  • Contraindications to treatment identified by laboratory tests, physical examination, medical history, or other investigations
  • severe hypotension (diastolic < 50 mm Hg or systolic < 90 mm Hg);
  • Clinically significant aortic or mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, fatal arrhythmias, LV ejection fraction < 45%, LV outflow tract obstruction, symptomatic coronary heart disease, spontaneously low blood pressure;
  • A history of malignancy within 5 years prior to enrollment, except for basal cell carcinoma of the skin and carcinoma in situ of the cervix;
  • Subject taking endothelin receptor antagonists such as ambrisentan, bosentan and macitentan within 4 weeks prior to enrollment;
  • pregnant and lactating women;
  • Subject deemed unsuitable for participation in this study by other investigators

Sites / Locations

  • Renji Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ambrisentan

Arm Description

Open Label

Outcomes

Primary Outcome Measures

Change From Baseline to 12 weeks and 24weeks in 6-minute Walk Distance
The 6-minute walk test (6MWT) is a non-encouraged test, performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. These guidelines were provided to all sites. For patients who had never performed a 6MWT previously, a training test was required before the qualifying tests for inclusion were performed.

Secondary Outcome Measures

Time to Clinical Worsening of Pulmonary Arterial Hypertension (PAH) up to Week 24, Assessed as the First Occurrence of a Clinical Worsening Events
Clinical Worsening Events included a 15% decrease from baseline on the 6-minute walk test, hospitalization for pulmonary hypertension complications, dosing or escalation of pulmonary hypertension-targeted drugs, atrial septostomy, lung transplantation, or death. Time to clinical worsening of PAH is the time from baseline to the first clinical occurrence of a Clinical Worsening Events.
Change from baseline to week 12 and 24 in Borg Dyspnea Index (BDI) sores
The BDI was calculated by using a 10-point scale (0 = None, 10 = Maximum).
Number of participants with a change from baseline to week 12 and 24 in WHO functional class
The WHO FC was determined by the investigator as follows: Class I - Participants with pulmonary hypertension (PH) but without resulting limitation of physical activity; II- Participants with PH resulting in slight limitation of physical activity; III - Participants with PH resulting in marked limitation of physical activity; IV - Participants with PH with inability to carry out any physical activity without symptoms.
Changes from baseline to week 12 and 24 in BNP plasma levels
BNP is a surrogate maker of heart failure.
Number and severity of Participants With Any Adverse Events
An adverse event is defined as any adverse medical event in a patient that is not necessarily causally related to treatment. An adverse event can thus be any adverse or non-therapeutic sign (including abnormal laboratory results), symptom or disease temporally related to the use of the drug product, whether or not considered drug-related.

Full Information

First Posted
June 24, 2022
Last Updated
June 28, 2022
Sponsor
RenJi Hospital
Collaborators
Shanghai Zhongshan Hospital, The First Affiliated Hospital with Nanjing Medical University, Shanghai Pulmonary Hospital, Shanghai, China, Xinqiao Hospital of Chongqing, The Affiliated Hospital of Qingdao University, First Affiliated Hospital of Chongqing Medical University, Wuhan Asia Heart Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05437224
Brief Title
Efficacy and Safety Study of Ambrisentan in Chinese Patients With Pulmonary Arterial Hypertension
Acronym
AMBLE
Official Title
A Multicenter Open Label Study to Evaluate Efficacy and Safety of China Made Ambrisentan in Chinese Patients With Pulmonary Arterial Hypertension
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
December 18, 2018 (Actual)
Primary Completion Date
January 9, 2022 (Actual)
Study Completion Date
February 6, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
RenJi Hospital
Collaborators
Shanghai Zhongshan Hospital, The First Affiliated Hospital with Nanjing Medical University, Shanghai Pulmonary Hospital, Shanghai, China, Xinqiao Hospital of Chongqing, The Affiliated Hospital of Qingdao University, First Affiliated Hospital of Chongqing Medical University, Wuhan Asia Heart Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This multicenter, open label, single-arm study is aim at investigating the the efficacy and safety of china made ambrisentan in Chinese subjects with PAH.
Detailed Description
Pulmonary arterial hypertension is a hemodynamic and pathophysiological state, which can cause progressive hyperplasia of pulmonary vascular walls and elevated pulmonary arterial pressure for various reasons. Ambrisentan is a selective endothelin-A (ETA) receptor antagonist with vasodilatory, antiproliferative and vascular remodeling effects at a dose of 5 mg or 10 mg once daily, oral. A number of international clinical studies have shown that ambrisentan can improve the hemodynamic parameters, WHO functional classification and exercise tolerance of PAH patients, and improve the survival rate. The domestic Ambrisentan tablet is produced by Jiangsu Hansoh Pharmaceutical Group Co., Ltd. under the trade name of "Pu Nuo An". It has been developed and completed according to the consistency evaluation standard after the bioequivalence test, and is currently listed in mainland China. In view of the low price of the domestic ambrisentan, in order to verify its efficacy and safety in the real world, this post-marketing multicenter clinical study was carried out.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Arterial Hypertension
Keywords
PAH, ambrisentan

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
80 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ambrisentan
Arm Type
Experimental
Arm Description
Open Label
Intervention Type
Drug
Intervention Name(s)
Ambrisentan
Intervention Description
eligible subjects received 5 mg ambrisentan orally once daily for a 12-week primary evaluation period. Subjects then proceeded to a 12-week dose adjustment period during which dose titration to 10 mg was allowed.
Primary Outcome Measure Information:
Title
Change From Baseline to 12 weeks and 24weeks in 6-minute Walk Distance
Description
The 6-minute walk test (6MWT) is a non-encouraged test, performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. These guidelines were provided to all sites. For patients who had never performed a 6MWT previously, a training test was required before the qualifying tests for inclusion were performed.
Time Frame
Baseline, week 12 and week 24
Secondary Outcome Measure Information:
Title
Time to Clinical Worsening of Pulmonary Arterial Hypertension (PAH) up to Week 24, Assessed as the First Occurrence of a Clinical Worsening Events
Description
Clinical Worsening Events included a 15% decrease from baseline on the 6-minute walk test, hospitalization for pulmonary hypertension complications, dosing or escalation of pulmonary hypertension-targeted drugs, atrial septostomy, lung transplantation, or death. Time to clinical worsening of PAH is the time from baseline to the first clinical occurrence of a Clinical Worsening Events.
Time Frame
From Baseline to week 24
Title
Change from baseline to week 12 and 24 in Borg Dyspnea Index (BDI) sores
Description
The BDI was calculated by using a 10-point scale (0 = None, 10 = Maximum).
Time Frame
Baseline, week 12 and week 24
Title
Number of participants with a change from baseline to week 12 and 24 in WHO functional class
Description
The WHO FC was determined by the investigator as follows: Class I - Participants with pulmonary hypertension (PH) but without resulting limitation of physical activity; II- Participants with PH resulting in slight limitation of physical activity; III - Participants with PH resulting in marked limitation of physical activity; IV - Participants with PH with inability to carry out any physical activity without symptoms.
Time Frame
Baseline, week 12 and week 24
Title
Changes from baseline to week 12 and 24 in BNP plasma levels
Description
BNP is a surrogate maker of heart failure.
Time Frame
Baseline, week 12 and week 24
Title
Number and severity of Participants With Any Adverse Events
Description
An adverse event is defined as any adverse medical event in a patient that is not necessarily causally related to treatment. An adverse event can thus be any adverse or non-therapeutic sign (including abnormal laboratory results), symptom or disease temporally related to the use of the drug product, whether or not considered drug-related.
Time Frame
From Baseline to week 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥18 years old and ≤75 years old, regardless of gender; patients weighing ≥ 40 kg; Patients diagnosed with PAH in Group 1 of the WHO Updated Clinical Classification of Pulmonary Hypertension (WHO functional class II or III); 6 min walk test (6MWT), walking distance ≥ 50 m; Right heart catheterization performed within 6 months prior to screening and meeting the following hemodynamic criteria: mean pulmonary artery pressure ≥ 25 mm Hg； Pulmonary vascular resistance ≥ 240 dyn·s·cm-5; Pulmonary artery wedge pressure or left ventricular end-diastolic pressure ≤ 15 mmHg; Subject receiving calcium channel blocker (CCB) drugs, only those whose doses have been stabilized for more than 4 weeks at the time of screening are allowed to be included in the study; Pulmonary function testing performed within 6 months prior to screening and meeting the following criteria： Total lung capacity ≥ 60% of normal predicted value; Forced expiratory volume in one second (FEV1) ≥ 55% of normal expected value; Female subjects of childbearing potential must have a negative pregnancy test at the Screening Visit and Day 0; Females subjects of childbearing potential must use a medically acceptable method of contraception (eg, hormone therapy, IUD, barrier methods such as condoms or cervical caps) during the study; Sign written informed consent Exclusion Criteria: Patients diagnosed with WHO updated PH clinical classification of group 2, 3, 4, 5; Endothelin receptor antagonist therapy (eg, bosentan) has been discontinued prior to enrollment due to safety or tolerability concerns (non-drug-induced liver function abnormalities); Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 2 times ULN; Serum bilirubin level > 1.5 times ULN; severe hepatic insufficiency (Child-Pugh class C); severe renal insufficiency (creatinine clearance <30 mL/min); Hemoglobin concentration < 10 g/dL or hematocrit < 30%; Contraindications to treatment identified by laboratory tests, physical examination, medical history, or other investigations severe hypotension (diastolic < 50 mm Hg or systolic < 90 mm Hg); Clinically significant aortic or mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, fatal arrhythmias, LV ejection fraction < 45%, LV outflow tract obstruction, symptomatic coronary heart disease, spontaneously low blood pressure; A history of malignancy within 5 years prior to enrollment, except for basal cell carcinoma of the skin and carcinoma in situ of the cervix; Subject taking endothelin receptor antagonists such as ambrisentan, bosentan and macitentan within 4 weeks prior to enrollment; pregnant and lactating women; Subject deemed unsuitable for participation in this study by other investigators
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jieyan Shen, PhD
Organizational Affiliation
Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital
Official's Role
Study Chair
Facility Information:
Facility Name
Renji Hospital
City
Shanghai
ZIP/Postal Code
200127
Country
China

12. IPD Sharing Statement

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Efficacy and Safety Study of Ambrisentan in Chinese Patients With Pulmonary Arterial Hypertension

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