Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension
- Registration Number
- NCT00380068
- Lead Sponsor
- Gilead Sciences
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 224
- 18 years of age or older
- 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).
- 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
- Right heart catheterization completed prior to screening must meet pre-specified criteria
- 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.
- 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
- Participation in a previous clinical study with ambrisentan
- Bosentan or sitaxsentan use within four weeks prior to the screening visit
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) lab value that is greater than 3 times the upper limit of normal at the screening visit
- 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
- Contraindication to treatment with endothelin receptor antagonist (ERA)
- History of malignancies other than basal cell carcinoma of the skin or in situ carcinoma of the cervix within the past five years
- Female participant who is pregnant or breastfeeding
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Ambrisentan Ambrisentan -
- Primary Outcome Measures
Name Time Method Change From Baseline to Week 24 in 6 Minute Walk Distance (6MWD) Baseline to Week 24
- Secondary Outcome Measures
Name Time Method Percent Change From Baseline to Week 24 in B-type Natriuretic Peptide (BNP) Baseline to Week 24 Change From Baseline to Week 24 in Borg Dyspnea Index Baseline to Week 24 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.
Change From Baseline to Week 48 in Borg Dyspnea Index Baseline to Week 48 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.
Percent Change From Baseline to Week 48 in BNP Baseline to Week 48 Change From Baseline to Week 24 in WHO Functional Class Baseline to Week 24 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.
Change From Baseline to Week 48 in WHO Functional Class Baseline to Week 48 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.
Change From Baseline to Week 24 in SF-36 Health Survey Physical Functioning Scale Baseline to Week 24 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.
Change From Baseline to Week 48 in SF-36 Health Survey Physical Functioning Scale Baseline to Week 48 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.
Percent of Participants With no Clinical Worsening of Pulmonary Hypertension (PH) at Week 24 Baseline to 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
Failure-free Treatment Status Baseline to Week 48 Defined by occurrence of death, lung transplantation, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents
Monotherapy Treatment Status Baseline to Week 48 Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment
Percent of Participants With no Clinical Worsening of PH at Week 48 Baseline to 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
Long-term Survival Baseline to Week 48 Defined as not dying during study participation
Trial Locations
- Locations (39)
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
🇺🇸Torrance, California, United States
University of Chicago Hospitals
🇺🇸Chicago, Illinois, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
Tufts-New England Medical Center
🇺🇸Boston, Massachusetts, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Boston Adult Congenital Heart Service
🇺🇸Boston, Massachusetts, United States
Boston University School of Medicine
🇺🇸Boston, Massachusetts, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
University of Pittsburgh Medical Center Presbyterian
🇺🇸Pittsburgh, Pennsylvania, United States
Lexington Pulmonary and Critical Care
🇺🇸Lexington, South Carolina, United States
University of Virginia Health Sciences Center
🇺🇸Charlottesville, Virginia, United States
Peter Lougheed Centre
🇨🇦Calgary, Alberta, Canada
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
University of Connecticut Health Center
🇺🇸Farmington, Connecticut, United States
University of Medicine & Dentistry of New Jersey
🇺🇸Newark, New Jersey, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Arizona Pulmonary Specialists, Ltd
🇺🇸Phoenix, Arizona, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
University of Colorado Health Sciences Center
🇺🇸Aurora, Colorado, United States
Greater Los Angeles, VA Medical Center
🇺🇸Los Angeles, California, United States
UCSD Medical Center, Thornton Hospital
🇺🇸La Jolla, California, United States
Pulmonary Hypertension Clinic Mount Sinai Medical Center
🇺🇸Miami Beach, Florida, United States
Suncoast Lung Center
🇺🇸Sarasota, Florida, United States
Atlanta Institute for Medical Research, Inc.
🇺🇸Decatur, Georgia, United States
Mary Parkes Asthma Center
🇺🇸Rochester, New York, United States
The Lindner Clinical Trial Center
🇺🇸Cincinnati, Ohio, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
New York Presbyterian Pulmonary Hypertension Center
🇺🇸New York, New York, United States
Medical College of Georgia
🇺🇸Augusta, Georgia, United States
Legacy Clinical Northwest
🇺🇸Portland, Oregon, United States
St. Vincent's Hospital
🇦🇺Darlinghurst, New South Wales, Australia
Allegheny General Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
Royal Perth Hospital
🇦🇺Perth, Australia
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
University of Alberta Hospitals
🇨🇦Edmonton, Alberta, Canada
University Hospitals of Cleveland
🇺🇸Cleveland, Ohio, United States
Washington University School of Medicine
🇺🇸St. Louis, Missouri, United States
Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States