Clinical trial NCT00617305: Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
Official title: An Open-label, Multicenter Study of Ambrisentan and a Phosphodiesterase Type-5 Inhibitor Combination Therapy in Subjects With Pulmonary Arterial Hypertension Who Have Demonstrated a Sub-Optimal Response to a Phosphodiesterase Type-5 Inhibitor
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pulmonary Arterial Hypertension
Keywords: ambrisentan
PAH
combination therapy
phosphodiesterase type-5 inhibitor (PDE-5i)
cardiovascular
endothelin receptor antagonist
ERA
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2008-02-18
Enrollment: 38
Sex: ALL
Minimum age (years): 16
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To evaluate the change from baseline in pulmonary vascular resistance (PVR), and other hemodynamic parameters, following the addition of ambrisentan to background phosphodiesterase type-5 inhibitor (PDE-5i) therapy in subjects with pulmonary arterial hypertension (PAH) who have demonstrated a sub-optimal response to PDE-5i monotherapy.

The study was originally designed as a 2-arm, double-blind, randomized study in which patients received ambrisentan or placebo for 24 weeks, and then received ambrisentan blinded to dose for 24 weeks. With Protocol Amendment 2 (12 June, 2009), the study was switched to single-arm, open-label treatment, and all patients remaining in the placebo arm were switched to open-label ambrisentan treatment. Patients who enrolled after Amendment 2 all received open-label ambrisentan.

Detailed description: The primary objective of this study is to evaluate the change from baseline in pulmonary vascular resistance (PVR), and other hemodynamic parameters, following the addition of ambrisentan to background phosphodiesterase type-5 inhibitor (PDE-5i) therapy in subjects with pulmonary arterial hypertension (PAH) who have demonstrated a sub-optimal response to PDE-5i monotherapy.

The secondary objectives of this study are to evaluate the change from baseline in other clinical measures of PAH following the addition of ambrisentan to background PDE-5i therapy in subjects with PAH who have demonstrated a sub-optimal response to PDE-5i monotherapy.

The safety and tolerability of ambrisentan/PDE-5i combination therapy will be evaluated throughout the study. In addition, long-term efficacy will be examined.

Eligibility criteria: Selected Inclusion Criteria

* Must be between 16 and 75 years of age;
* Must weigh at least 40 kg;
* Have a current diagnosis of idiopathic PAH, familial PAH, or PAH that is primarily due to connective tissue disease, congenital heart defects, drug or toxin use, or human immunodeficiency virus (HIV);
* Have WHO functional class III symptoms;
* Be receiving sildenafil or tadalafil monotherapy for the treatment of PAH for at least the past 12 weeks and at a stable dose for at least 8 consecutive weeks;
* Meet all of the following hemodynamic criteria by means of a right heart catheterization: mPAP of at least 25 mmHg; PVR of at least 400 dyne\*sec/cm5; pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) of not more than 15 mmHg;
* Meet all of the following pulmonary function test criteria no more than 12 weeks before the screening visit: total lung capacity at least 60% of predicted normal and forced expiratory volume in 1 second of at least 65% of predicted normal;
* Able to walk at least 150 meters during the screening 6-minute walk test (6MWT);
* If receiving calcium channel blockers or 5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (i.e., statins) must be on stable therapy for at least 4 weeks;
* If diagnosed with HIV, must have stable disease status.

Selected Exclusion Criteria:

* Have a current pulmonary hypertension diagnosis other than idiopathic PAH, familial PAH, or PAH that is primarily due to connective tissue disease, congenital heart defects, drug or toxin use, or HIV;
* Have left ventricular ejection fraction (LVEF) ≤40% or clinically significant ischemic, valvular, or constrictive heart disease;
* Have received chronic prostanoid or endothelin receptor antagonist (ERA) therapy (eg, bosentan, sitaxsentan) within the past 12 weeks;
* Have discontinued ERA treatment for any adverse reaction other than those associated with liver function test abnormalities;
* Have received IV inotropes within 2 weeks;
* Have a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value that is greater than 2.0x the upper limit of normal.

Primary outcomes:
measure: Change From Baseline in Pulmonary Vascular Resistance (PVR), Last Observation Carried Forward (LOCF)
timeFrame: Baseline to Week 24
Secondary outcomes:
measure: Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) (LOCF)
timeFrame: Baseline to Week 24
measure: Change From Baseline in Mean Right Atrial Pressure (mRAP) (LOCF)
timeFrame: Baseline to Week 24
measure: Change From Baseline in Cardiac Output (LOCF)
timeFrame: Baseline to Week 24
measure: Change From Baseline in Six Minute Walk Distance (6MWD) Measured at Weeks 4, 12, 24, 36 and 48 (LOCF)
timeFrame: Baseline to Week 48
measure: Change in Dyspnea Index Measured at Weeks 4, 12, 24, 36 and 48 (LOCF)
timeFrame: Baseline to Week 48
measure: Change From Baseline in the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Quality of Life (QOL) Survey Overall Score Measured at Weeks 12, 24, 36 and 48 (LOCF)
timeFrame: Baseline to Week 48
measure: Change From Baseline in World Health Organization (WHO) Functional Class (LOCF) Measured at Weeks 4, 12, 24, 36 and 48.
timeFrame: Baseline to Week 48
measure: Change From Baseline in Log-transformed N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Measured at Weeks 4, 12, 24, 36 and 48 (LOCF)
timeFrame: Baseline to Week 48
measure: Time to Clinical Worsening of PAH, Evaluated at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and After Week 48
timeFrame: Baseline to Week 48+
measure: Overall Survival, Evaluated at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and After Week 48
timeFrame: Baseline to Week 48+
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of South Alabama
state: Alabama
city: Phoenix
country: United States
facility: Arizona Pulmonary Specialists
state: Arizona
city: Los Angeles
country: United States
facility: West Los Angeles Healthcare Center
state: California
city: Torrance
country: United States
facility: Harbor - UCLA
state: California
city: Ft. Lauderdale
country: United States
facility: Cleveland Clinic
state: Florida
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: Orlando
country: United States
facility: Orlando Heart Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Decatur
country: United States
facility: Atlanta Institute for Medical Research
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: BACH Cardiology
state: Massachusetts
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
city: Asheville
country: United States
facility: Asheville Cardiology Associates
state: North Carolina
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
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: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Temple
country: United States
facility: Scott & White Memorial Hospital
state: Texas
city: Norfolk
country: United States
facility: Sentara Norfolk General Hospital
state: Virginia
Study officials:
References: