Clinical trial NCT00380068: Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension
Official title: ARIES-3: A Phase 3, Long-Term, Open-Label, Multicenter Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Hypertension
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2006-09-25
Enrollment: 224
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline to Week 24 in 6 Minute Walk Distance (6MWD)
timeFrame: Baseline to Week 24
Secondary outcomes:
measure: Change From Baseline to Week 24 in Borg Dyspnea Index
timeFrame: Baseline to Week 24
measure: Change From Baseline to Week 48 in Borg Dyspnea Index
timeFrame: Baseline to Week 48
measure: Percent Change From Baseline to Week 24 in B-type Natriuretic Peptide (BNP)
timeFrame: Baseline to Week 24
measure: Percent Change From Baseline to Week 48 in BNP
timeFrame: Baseline to Week 48
measure: Change From Baseline to Week 24 in WHO Functional Class
timeFrame: Baseline to Week 24
measure: Change From Baseline to Week 48 in WHO Functional Class
timeFrame: Baseline to Week 48
measure: Change From Baseline to Week 24 in SF-36 Health Survey Physical Functioning Scale
timeFrame: Baseline to Week 24
measure: Change From Baseline to Week 48 in SF-36 Health Survey Physical Functioning Scale
timeFrame: Baseline to Week 48
measure: Percent of Participants With no Clinical Worsening of Pulmonary Hypertension (PH) at Week 24
timeFrame: Baseline to Week 24
measure: Percent of Participants With no Clinical Worsening of PH at Week 48
timeFrame: Baseline to Week 48
measure: Failure-free Treatment Status
timeFrame: Baseline to Week 24
measure: Failure-free Treatment Status
timeFrame: Baseline to Week 48
measure: Monotherapy Treatment Status
timeFrame: Baseline to Week 24
measure: Monotherapy Treatment Status
timeFrame: Baseline to Week 48
measure: Long-term Survival
timeFrame: Baseline to Week 24
measure: Long-term Survival
timeFrame: Baseline to Week 48
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Arizona Pulmonary Specialists, Ltd
state: Arizona
city: La Jolla
country: United States
facility: UCSD Medical Center, Thornton Hospital
state: California
city: Los Angeles
country: United States
facility: Greater Los Angeles, VA Medical Center
state: California
city: Torrance
country: United States
facility: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Health Sciences Center
state: Colorado
city: Farmington
country: United States
facility: University of Connecticut Health Center
state: Connecticut
city: Miami Beach
country: United States
facility: Pulmonary Hypertension Clinic Mount Sinai Medical Center
state: Florida
city: Sarasota
country: United States
facility: Suncoast Lung Center
state: Florida
city: Augusta
country: United States
facility: Medical College of Georgia
state: Georgia
city: Decatur
country: United States
facility: Atlanta Institute for Medical Research, Inc.
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Hospitals
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Tufts-New England Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Adult Congenital Heart Service
state: Massachusetts
city: Boston
country: United States
facility: Boston University School of Medicine
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Newark
country: United States
facility: University of Medicine & Dentistry of New Jersey
state: New Jersey
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: New York
country: United States
facility: New York Presbyterian Pulmonary Hypertension Center
state: New York
city: Rochester
country: United States
facility: Mary Parkes Asthma Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: The Lindner Clinical Trial Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
city: Portland
country: United States
facility: Legacy Clinical Northwest
state: Oregon
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center Presbyterian
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Lexington
country: United States
facility: Lexington Pulmonary and Critical Care
state: South Carolina
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health Sciences Center
state: Virginia
city: Darlinghurst
country: Australia
facility: St. Vincent's Hospital
state: New South Wales
city: Perth
country: Australia
facility: Royal Perth Hospital
city: Calgary
country: Canada
facility: Peter Lougheed Centre
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospitals
state: Alberta
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
Study officials:
affiliation: University of California, San Diego
name: Lewis J Rubin, MD
role: PRINCIPAL_INVESTIGATOR
References: