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

NCT00617305 | Completed Phase 4 Results DMC

• 1 other identifier: GS-US-300-0117
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 30

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.

Conditions

Pulmonary Arterial Hypertension

Keywords

ambrisentan; PAH; combination therapy; phosphodiesterase type-5 inhibitor (PDE-5i); cardiovascular; endothelin receptor antagonist; ERA

Outcome Measures

Primary Outcomes (1)

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

  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.

  Baseline to Week 24

Secondary Outcomes (10)

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

  Baseline to Week 24

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

  Baseline to Week 24

• Change From Baseline in Cardiac Output (LOCF)

  Baseline to Week 24

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

  Baseline to Week 48

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

  Baseline to Week 48

Study Arms (2)

Ambrisentan

EXPERIMENTAL

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).

Drug: Ambrisentan; Drug: Sildenafil; Drug: Tadalafil

Placebo

ACTIVE COMPARATOR

Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (sildenafil or tadalafil).

Drug: Placebo; Drug: Sildenafil; Drug: Tadalafil

Interventions

Ambrisentan DRUG

Ambrisentan was administered orally once daily; dose level was 5 mg for the first 4 weeks, followed by 10 mg for the remainder of the study; ambrisentan was supplied as 5-mg and 10-mg tablets.

Also known as: Letairis

Ambrisentan

Placebo DRUG

Placebo to match ambrisentan was administered orally once daily.

Placebo

Sildenafil DRUG

Sildenafil was administered at the dose previously established for each subject (20-100 mg) orally three times daily. Sildenafil was supplied as 20-mg tablets, or formulated as sildenafil citrate in 25-, 50-, or 100-mg tablets.

Also known as: Revatio, Viagra

Ambrisentan; Placebo

Tadalafil DRUG

Tadalafil was administered at the dose previously established for each subject (not to exceed 40 mg per day) orally once daily. Tadalafil was supplied as 20-mg tablets.

Also known as: Cialis, Adcirca

Ambrisentan; Placebo

Eligibility Criteria

• Age: 16 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (30)

University of South Alabama

Mobile, Alabama, 36617, United States

Location

Arizona Pulmonary Specialists

Phoenix, Arizona, 85013, United States

Location

West Los Angeles Healthcare Center

Los Angeles, California, 90073, United States

Location

Harbor - UCLA

Torrance, California, 90502, United States

Location

Cleveland Clinic

Fort Lauderdale, Florida, 33331, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

Mount Sinai Medical Center

Miami Beach, Florida, 33140, United States

Location

Orlando Heart Center

Orlando, Florida, 32806, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Atlanta Institute for Medical Research

Decatur, Georgia, 30030, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

University of Maryland

Baltimore, Maryland, 21201, United States

Location

BACH Cardiology

Boston, Massachusetts, 02115, United States

Location

Brigham & Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Wayne State University

Detroit, Michigan, 48201, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Weill Cornell Medical Center

New York, New York, 10021, United States

Location

Asheville Cardiology Associates

Asheville, North Carolina, 28803, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

The Lindner Clinical Trial Center

Cincinnati, Ohio, 45219, United States

Location

University Hospitals of Cleveland

Cleveland, Ohio, 44106, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Altoona Center for Clinical Research

Duncansville, Pennsylvania, 16635, United States

Location

Allegheny General Hospital

Pittsburgh, Pennsylvania, 15212, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

Rhode Island Hospital

Providence, Rhode Island, 02903, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75235, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Scott & White Memorial Hospital

Temple, Texas, 76508, United States

Location

Sentara Norfolk General Hospital

Norfolk, Virginia, 23507, United States

Location

Related Links

• Click here for more information about ambrisentan

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

ambrisentan; Sildenafil Citrate; Tadalafil

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Carbolines; Pyridines; Indole Alkaloids; Indoles; Heterocyclic Compounds, 3-Ring

Results Point of Contact

• Title: Ellen Shen, PhD, Senior Manager, Regulatory Affairs
• Organization: Gilead Sciences

Ellen.Shen@gilead.com

+1 (650) 522-5278

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2008
• First Posted: February 18, 2008
• Study Start: April 1, 2008
• Primary Completion: February 1, 2011
• Study Completion: July 1, 2011
• Last Updated: July 30, 2012
• Results First Posted: July 30, 2012

Record last verified: 2012-06

Locations

US (30)