Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension

ARIES-3: A Phase 3, Long-Term, Open-Label, Multicenter Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension

The primary objective of this study was to evaluate the safety and efficacy of ambrisentan in a broad population of participants with pulmonary hypertension (PH). Secondary objectives of this study were to evaluate the effects of ambrisentan on other clinical measures of pulmonary arterial hypertension (PAH), long-term treatment success, and survival.

Study Overview

• Status: Completed
• Conditions: Pulmonary Hypertension
• Intervention / Treatment: Drug: Ambrisentan

Detailed Description

This study was to enroll up to 200 participants with PH due to the following etiologies: 1) PAH including idiopathic and familial PAH and PAH associated with collagen vascular disease, congenital systemic-to-pulmonary shunts (including Eisenmenger's syndrome), human immunodeficiency virus (HIV) infection, drugs and toxins, thyroid disorders, glycogen storage disease, Gaucher disease, hemoglobinopathies, and splenectomy (WHO Group 1); 2) PH associated with lung diseases and/or hypoxemia, including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), sleep-disordered breathing, and alveolar hypoventilation disorders (WHO Group 3); 3) PH due to proximal or distal chronic thromboembolic obstruction (WHO Group 4); and 4) PH due to sarcoidosis (WHO Group 5). Participants with left heart disease or left heart failure were excluded (WHO Group 2). Participants could be receiving prostacyclin or sildenafil therapy at baseline, and participants who previously discontinued either bosentan, sitaxsentan, or both, due to liver function test abnormalities were eligible.

• Study Type: Interventional
• Enrollment (Actual): 224
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Perth, Australia, 6000
    • Royal Perth Hospital
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St. Vincent's Hospital
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
      • Peter Lougheed Centre
    • Edmonton, Alberta, Canada, T6G 2B7
      • University Of Alberta Hospitals
  • Ontario
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Arizona Pulmonary Specialists, Ltd
  • California
    • La Jolla, California, United States, 92037
      • UCSD Medical Center, Thornton Hospital
    • Los Angeles, California, United States, 90073
      • Greater Los Angeles, VA Medical Center
    • Torrance, California, United States, 90502
      • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Health Sciences Center
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • University of Connecticut Health Center
  • Florida
    • Miami Beach, Florida, United States, 33140
      • Pulmonary Hypertension Clinic Mount Sinai Medical Center
    • Sarasota, Florida, United States, 34233
      • Suncoast Lung Center
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Medical College of Georgia
    • Decatur, Georgia, United States, 30030
      • Atlanta Institute for Medical Research, Inc.
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Hospitals
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02118
      • Boston University School Of Medicine
    • Boston, Massachusetts, United States, 02111
      • Tufts-New England Medical Center
    • Boston, Massachusetts, United States, 02115
      • Boston Adult Congenital Heart Service
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
    • Newark, New Jersey, United States, 07103
      • University of Medicine & Dentistry of New Jersey
  • New York
    • New York, New York, United States, 10032
      • New York Presbyterian Pulmonary Hypertension Center
    • Rochester, New York, United States, 14623
      • Mary Parkes Asthma Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Clinical Trial Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals of Cleveland
  • Oregon
    • Portland, Oregon, United States, 97210
      • Legacy Clinical Northwest
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center Presbyterian
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Lexington, South Carolina, United States, 29072
      • Lexington Pulmonary and Critical Care
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health Sciences Center

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

Summarized Inclusion Criteria:

1. 18 years of age or older
2. Current diagnosis of PH associated with an acceptable etiology as outlined in the protocol, including: PH due to the following etiologies: 1) PAH including idiopathic and familial PAH and PAH associated with collagen vascular disease, congenital systemic-to-pulmonary shunts (including Eisenmenger's syndrome), human immunodeficiency virus (HIV) infection, drugs and toxins, thyroid disorders, glycogen storage disease, Gaucher disease, hemoglobinopathies, and splenectomy (WHO Group 1); 2) PH associated with lung diseases and/or hypoxemia, including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), sleep-disordered breathing, and alveolar hypoventilation disorders (WHO Group 3); 3) PH due to proximal or distal chronic thromboembolic obstruction (WHO Group 4); and 4) PH due to sarcoidosis (WHO Group 5).
3. Stable regimen (within four weeks) of chronic prostanoid, PDE-5 inhibitor, calcium channel blocker, or 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor therapy
4. Right heart catheterization completed prior to screening must meet pre-specified criteria
5. Female participants of childbearing potential must have a negative serum pregnancy test and must agree to use a reliable double method of contraception until study completion and for at least four weeks following their final study visit.
6. Male participants must be informed of the potential risks of testicular tubular atrophy and infertility associated with taking ambrisentan and queried regarding his understanding of the potential risks as described in the Informed Consent Form.

Summarized Exclusion Criteria:

1. Participation in a previous clinical study with ambrisentan
2. Bosentan or sitaxsentan use within four weeks prior to the screening visit
3. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) lab value that is greater than 3 times the upper limit of normal at the screening visit
4. Pulmonary function tests not meeting the following pre-specified criteria: 1) mean pulmonary arterial pressure (PAP) >= 25 mm Hg; 2) PVR > 3 mm Hg/L/min; 3) pulmonary capillary wedge pressure (PCWP) or left ventricle end diastolic pressure (LVEDP) < 15 mm Hg; 4) total lung capacity (TLC) >= 70% of predicted normal for participants without ILD or >= 60% of predicted normal in participants with ILD; forced expiratory volume in 1 second (FEV1) >= 65% of predicted normal in participants without COPD or >= 50% of predicted normal in participants with COPD
5. Contraindication to treatment with endothelin receptor antagonist (ERA)
6. History of malignancies other than basal cell carcinoma of the skin or in situ carcinoma of the cervix within the past five years
7. Female participant who is pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ambrisentan	Drug: Ambrisentan; Oral tablets taken once daily.; Other Names: Letairis; Volibris

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change From Baseline to Week 24 in 6 Minute Walk Distance (6MWD)	Baseline to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 24 in Borg Dyspnea Index	Change from Baseline to Week 24 in Borg Dyspnea Index. The Borg Dyspnea Index of Perceived Exertion Scores range from 0 to 10. Best and Worst values are: 0 (Best) to 10 (Worst). Scales are described as rating of breathlessness and its description: 0= none; 0.5= very,very slight (just noticeable); 1= very slight; 2=slight; 3= moderate; 4= somewhat severe; 5= severe; 6 (in between severe and very severe); 7= very severe; 8 (in between very, very severe and maximum); 9= very, very severe; and 10= maximum.	Baseline to Week 24
Change From Baseline to Week 48 in Borg Dyspnea Index	Change from Baseline to Week 48 in Borg Dyspnea Index. The Borg Dyspnea Index of Perceived Exertion Scores range from 0 to 10. Best and Worst values are: 0 (Best) to 10 (Worst). Scales are described as rating of breathlessness and its description: 0= none; 0.5= very,very slight (just noticeable); 1= very slight; 2=slight; 3= moderate; 4= somewhat severe; 5= severe; 6 (in between severe and very severe); 7= very severe; 8 (in between very, very severe and maximum); 9= very, very severe; and 10= maximum.	Baseline to Week 48
Percent Change From Baseline to Week 24 in B-type Natriuretic Peptide (BNP)		Baseline to Week 24
Percent Change From Baseline to Week 48 in BNP		Baseline to Week 48
Change From Baseline to Week 24 in WHO Functional Class	Change from baseline in World Health Organization functional class (WHO) at Week 24 is the incidence of participants that improved, had no change, or worsened. WHO categories are 1 to 4 with the worse category at 4. Improvement = a category change from baseline of <= -1: change of -3 (eg, WHO from 4 to 1), change of -2 (eg, WHO from 3 to 1), change of -1 (eg, WHO from 2 to 1). Inversely, participants worsening are those with a category change from baseline of at least +1. No change in WHO functional class represents the percentage of participants with a change in category from baseline of 0.	Baseline to Week 24
Change From Baseline to Week 48 in WHO Functional Class	Change from baseline in WHO at Week 48 is expressed as the incidence of participants that improved, had no change or worsened. WHO categories range from 1 to 4 with the worse category at 4. Improvement = a category change from baseline of <= -1: change of -3 (eg, WHO from 4 to 1), change of -2 (eg, WHO from 3 to 1), change of -1 (eg, WHO from 2 to 1). Inversely, participants worsening are those with a category change from baseline of at least +1. No change in WHO functional class represents the percentage of participants with a change in category from baseline of 0.	Baseline to Week 48
Change From Baseline to Week 24 in SF-36 Health Survey Physical Functioning Scale	Change from baseline to Week 24 in the SF-36 health survey physical functioning scale. 10 activities rated by health limitations using 3 categories (1= Yes, limited a lot; 2= Yes, limited a little; and 3= No, not limited at all). The best score is 3 and the worst score is 1. Scores are transformed by subtracting the unit by the lowest raw score and dividing by the raw score range. The scores are then standardized with the 1998 General United States (US) population mean and standard deviation (SD). Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10.	Baseline to Week 24
Change From Baseline to Week 48 in SF-36 Health Survey Physical Functioning Scale	Change from baseline to Week 48 in the SF-36 health survey physical functioning scale. 10 activities are rated by health limitations using 3 categories (1= Yes, limited a lot; 2= Yes, limited a little; and 3= No, not limited at all). The best score is 3 and the worst score is 1. Scores are transformed by subtracting the unit by the lowest raw score and dividing by the raw score range. The scores are then standardized with the 1998 General US population mean and standard deviation. Finally, the scores are transformed to the norm-based scoring with a mean of 50 and standard deviation of 10.	Baseline to Week 48
Percent of Participants With no Clinical Worsening of Pulmonary Hypertension (PH) at Week 24	Clinical worsening: occurrence of death, lung transplantation, hospitalization for PH, atrial septostomy, a change to chronic prostanoid or sildenafil treatment due to protocol-defined worsening criteria, or study withdrawal due to the addition of other clinically approved PH therapeutic agents	Baseline to Week 24
Percent of Participants With no Clinical Worsening of PH at Week 48	Clinical worsening: occurrence of death, lung transplantation, hospitalization for PH, atrial septostomy, a change to chronic prostanoid or sildenafil treatment due to protocol-defined worsening criteria, or study withdrawal due to the addition of other clinically approved PH therapeutic agents	Baseline to Week 48
Failure-free Treatment Status	Defined by occurrence of death, lung transplantation, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents	Baseline to Week 24
Failure-free Treatment Status	Defined by occurrence of death, lung transplantation, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents	Baseline to Week 48
Monotherapy Treatment Status	Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment	Baseline to Week 24
Monotherapy Treatment Status	Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment	Baseline to Week 48
Long-term Survival	Defined as not dying during study participation	Baseline to Week 24
Long-term Survival	Defined as not dying during study participation	Baseline to Week 48

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Principal Investigator: Lewis J Rubin, MD, University of California, San Diego

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): July 1, 2008
• Study Completion (Actual): May 1, 2009

Study Registration Dates

• First Submitted: September 21, 2006
• First Submitted That Met QC Criteria: September 21, 2006
• First Posted (Estimate): September 25, 2006

Study Record Updates

• Last Update Posted (Estimate): April 5, 2012
• Last Update Submitted That Met QC Criteria: April 2, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary; Antihypertensive Agents; Ambrisentan
• Other Study ID Numbers: AMB-323; ARIES-3