Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
- Conditions
- Pulmonary Arterial Hypertension
- Interventions
- Registration Number
- NCT00617305
- Lead Sponsor
- Gilead Sciences
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 38
Not provided
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (sildenafil or tadalafil). Placebo Sildenafil Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (sildenafil or tadalafil). Placebo Tadalafil Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (sildenafil or tadalafil). Ambrisentan Ambrisentan Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i; sildenafil or tadalafil). Ambrisentan Sildenafil Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i; sildenafil or tadalafil). Ambrisentan Tadalafil Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i; sildenafil or tadalafil).
- Primary Outcome Measures
Name Time Method Change From Baseline in Pulmonary Vascular Resistance (PVR), Last Observation Carried Forward (LOCF) Baseline to Week 24 The primary objective of this study is to evaluate the change from baseline in PVR, and other hemodynamic parameters, 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. A decrease in measurement value (dynes sec/cm\^5) indicates improvement for this patient population.
- Secondary Outcome Measures
Name Time Method Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) (LOCF) Baseline to Week 24 This secondary hemodynamic outcome is supportive of the primary outcome. A decrease in measurement value (mmHg) indicates improvement for this patient population.
Change From Baseline in Mean Right Atrial Pressure (mRAP) (LOCF) Baseline to Week 24 This secondary hemodynamic outcome is supportive of the primary outcome. A decrease in measurement value (mmHg) indicates improvement for this patient population.
Change From Baseline in Cardiac Output (LOCF) Baseline to Week 24 This secondary hemodynamic outcome is supportive of the primary outcome. An increase in measurement value (L/min) indicates improvement for this patient population.
Change From Baseline in Six Minute Walk Distance (6MWD) Measured at Weeks 4, 12, 24, 36 and 48 (LOCF) Baseline to Week 48 The primary analysis of this secondary outcome measure is mean change from Baseline to Week 24. The changes from Baseline to Weeks 4, 12, 36, and 48 were also evaluated. An increase in measurement value (meters walked) indicates improvement for this patient population.
Change in Dyspnea Index Measured at Weeks 4, 12, 24, 36 and 48 (LOCF) Baseline to Week 48 The primary analysis of this secondary outcome measure is mean change from Baseline to Week 24. The changes from Baseline to Weeks 4, 12, 36, and 48 were also evaluated. The dyspnea index measures the degree of breathlessness after completion of the 6MWT using a scale of 0 to 10, with 0 indicating no breathlessness and 10 indicating maximum breathlessness.
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) Baseline to Week 48 The primary analysis of this secondary outcome measure is mean change from Baseline to Week 24. The changes from Baseline to Weeks 12, 36, and 48 were also evaluated. Lower scores and decreases from baseline represent improved functioning and QOL. The CAMPHOR survey was not assessed at Week 4. The total CAMPHOR score scale ranges from 0 (good) to 25 (poor). A reduction in score over time represents improvement in this patient population.
Change From Baseline in World Health Organization (WHO) Functional Class (LOCF) Measured at Weeks 4, 12, 24, 36 and 48. Baseline to Week 48 The primary analysis of this secondary outcome measure is change from Baseline to Week 24. The changes from Baseline to Weeks 4, 12, 36, and 48 were also evaluated. WHO categories are 1 to 4 with the worst category being 4. Improvement is represented by a change in category to a lower number (for example, change from category 3 to 2), and deterioration is represented by a change in category to a higher number (for example, change from category 2 to 4). No change is represented by no change in category (for example, category 2 which remains 2).
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) Baseline to Week 48 The primary analysis of this secondary outcome measure is mean percent change from Baseline to Week 24. The changes from Baseline to Weeks 4, 12, 36, and 48 were also evaluated. A decrease in log-transformed measurement value (pg/mL) indicates improvement for this patient population.
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 Baseline to Week 48+ The time to clinical worsening was defined as the time from enrollment to the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, or initiation of chronic parenteral prostanoid therapy. Results are presented as the Kaplan-Meier estimate (% probability) of having clinical worsening after a given time.
Overall Survival, Evaluated at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and After Week 48 Baseline to Week 48+ Overall survival was defined as the time from initiation of active treatment to death. Results are presented as the Kaplan-Meier estimate (% probability) of death after a given time.
Trial Locations
- Locations (30)
Scott & White Memorial Hospital
🇺🇸Temple, Texas, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
Emory University
🇺🇸Atlanta, Georgia, United States
University of Maryland
🇺🇸Baltimore, Maryland, United States
Allegheny General Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
University of Florida
🇺🇸Gainesville, Florida, United States
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
University of South Alabama
🇺🇸Mobile, Alabama, United States
Weill Cornell Medical Center
🇺🇸New York, New York, United States
West Los Angeles Healthcare Center
🇺🇸Los Angeles, California, United States
Harbor - UCLA
🇺🇸Torrance, California, United States
Atlanta Institute for Medical Research
🇺🇸Decatur, Georgia, United States
University of Pittsburgh Medical Center
🇺🇸Pittsburgh, Pennsylvania, United States
Altoona Center for Clinical Research
🇺🇸Duncansville, Pennsylvania, United States
Brigham & Women's Hospital
🇺🇸Boston, Massachusetts, United States
University Hospitals of Cleveland
🇺🇸Cleveland, Ohio, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
The Lindner Clinical Trial Center
🇺🇸Cincinnati, Ohio, United States
Arizona Pulmonary Specialists
🇺🇸Phoenix, Arizona, United States
Wayne State University
🇺🇸Detroit, Michigan, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Cleveland Clinic
🇺🇸Ft. Lauderdale, Florida, United States
Mount Sinai Medical Center
🇺🇸Miami Beach, Florida, United States
BACH Cardiology
🇺🇸Boston, Massachusetts, United States
Asheville Cardiology Associates
🇺🇸Asheville, North Carolina, United States
Ohio State University
🇺🇸Columbus, Ohio, United States
Sentara Norfolk General Hospital
🇺🇸Norfolk, Virginia, United States
Orlando Heart Center
🇺🇸Orlando, Florida, United States
University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States