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Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)

Information source: Gilead Sciences
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Pulmonary Arterial Hypertension

Intervention: Ambrisentan (Drug); Placebo (Drug); Sildenafil (Drug); Tadalafil (Drug)

Phase: Phase 4

Status: Completed

Sponsored by: Gilead Sciences

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.

Clinical Details

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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Change From Baseline in Pulmonary Vascular Resistance (PVR), Last Observation Carried Forward (LOCF)

Secondary outcome:

Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) (LOCF)

Change From Baseline in Mean Right Atrial Pressure (mRAP) (LOCF)

Change From Baseline in Cardiac Output (LOCF)

Change From Baseline in Six Minute Walk Distance (6MWD) Measured at Weeks 4, 12, 24, 36 and 48 (LOCF)

Change in Dyspnea Index Measured at Weeks 4, 12, 24, 36 and 48 (LOCF)

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)

Change From Baseline in World Health Organization (WHO) Functional Class (LOCF) Measured at Weeks 4, 12, 24, 36 and 48.

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)

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

Overall Survival, Evaluated at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and After Week 48

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

Minimum age: 16 Years. Maximum age: 75 Years. Gender(s): Both.

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.

Locations and Contacts

University of South Alabama, Mobile, Alabama 36617, United States

Arizona Pulmonary Specialists, Phoenix, Arizona 85013, United States

West Los Angeles Healthcare Center, Los Angeles, California 90073, United States

Harbor - UCLA, Torrance, California 90502, United States

Cleveland Clinic, Ft. Lauderdale, Florida 33331, United States

University of Florida, Gainesville, Florida 32610, United States

Mount Sinai Medical Center, Miami Beach, Florida 33140, United States

Orlando Heart Center, Orlando, Florida 32806, United States

Emory University, Atlanta, Georgia 30322, United States

Atlanta Institute for Medical Research, Decatur, Georgia 30030, United States

University of Iowa, Iowa City, Iowa 52242, United States

University of Maryland, Baltimore, Maryland 21201, United States

BACH Cardiology, Boston, Massachusetts 02115, United States

Brigham & Women's Hospital, Boston, Massachusetts 02115, United States

Wayne State University, Detroit, Michigan 48201, United States

Mayo Clinic, Rochester, Minnesota 55905, United States

Weill Cornell Medical Center, New York, New York 10021, United States

Asheville Cardiology Associates, Asheville, North Carolina 28803, United States

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States

The Lindner Clinical Trial Center, Cincinnati, Ohio 45219, United States

University Hospitals of Cleveland, Cleveland, Ohio 44106, United States

Ohio State University, Columbus, Ohio 43210, United States

Altoona Center for Clinical Research, Duncansville, Pennsylvania 16635, United States

Allegheny General Hospital, Pittsburgh, Pennsylvania 15212, United States

University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, United States

Rhode Island Hospital, Providence, Rhode Island 02903, United States

UT Southwestern Medical Center, Dallas, Texas 75235, United States

Baylor College of Medicine, Houston, Texas 77030, United States

Scott & White Memorial Hospital, Temple, Texas 76508, United States

Sentara Norfolk General Hospital, Norfolk, Virginia 23507, United States

Additional Information

Click here for more information about ambrisentan

Starting date: April 2008
Last updated: June 22, 2012

Page last updated: August 23, 2015

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