Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension

Pulmonary Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00380068
• Other study ID #: AMB-323
• Secondary ID: ARIES-3
• Status: Completed
• Phase: Phase 3
• First received: September 21, 2006
• Last updated: April 2, 2012
• Start date: August 2006
• Est. completion date: May 2009

Study information

• Verified date: April 2012
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 224
• Est. completion date: May 2009
• Est. primary completion date: July 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension

Intervention

Drug:
• Ambrisentan
Oral tablets taken once daily.

Locations

Country	Name	City	State
Australia	St. Vincent's Hospital	Darlinghurst	New South Wales
Australia	Royal Perth Hospital	Perth
Canada	Peter Lougheed Centre	Calgary	Alberta
Canada	University of Alberta Hospitals	Edmonton	Alberta
Canada	Toronto General Hospital	Toronto	Ontario
United States	Medical College of Georgia	Augusta	Georgia
United States	University of Colorado Health Sciences Center	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Boston Adult Congenital Heart Service	Boston	Massachusetts
United States	Boston University School of Medicine	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts-New England Medical Center	Boston	Massachusetts
United States	University of Virginia Health Sciences Center	Charlottesville	Virginia
United States	University of Chicago Hospitals	Chicago	Illinois
United States	The Lindner Clinical Trial Center	Cincinnati	Ohio
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	Atlanta Institute for Medical Research, Inc.	Decatur	Georgia
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Connecticut Health Center	Farmington	Connecticut
United States	Baylor College of Medicine	Houston	Texas
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	UCSD Medical Center, Thornton Hospital	La Jolla	California
United States	Lexington Pulmonary and Critical Care	Lexington	South Carolina
United States	Greater Los Angeles, VA Medical Center	Los Angeles	California
United States	Pulmonary Hypertension Clinic Mount Sinai Medical Center	Miami Beach	Florida
United States	New York Presbyterian Pulmonary Hypertension Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	University of Medicine & Dentistry of New Jersey	Newark	New Jersey
United States	Arizona Pulmonary Specialists, Ltd	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	University of Pittsburgh Medical Center Presbyterian	Pittsburgh	Pennsylvania
United States	Legacy Clinical Northwest	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Mary Parkes Asthma Center	Rochester	New York
United States	Mayo Clinic	Rochester	Minnesota
United States	Suncoast Lung Center	Sarasota	Florida
United States	Washington University School of Medicine	St. Louis	Missouri
United States	Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline to Week 24 in 6 Minute Walk Distance (6MWD)		Baseline to Week 24	No
Secondary	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	No
Secondary	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	No
Secondary	Percent Change From Baseline to Week 24 in B-type Natriuretic Peptide (BNP)		Baseline to Week 24	No
Secondary	Percent Change From Baseline to Week 48 in BNP		Baseline to Week 48	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Monotherapy Treatment Status	Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment	Baseline to Week 24	No
Secondary	Monotherapy Treatment Status	Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment	Baseline to Week 48	No
Secondary	Long-term Survival	Defined as not dying during study participation	Baseline to Week 24	No
Secondary	Long-term Survival	Defined as not dying during study participation	Baseline to Week 48	No

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