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

Gilead Sciences38 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Interventions

AmbrisentanDRUG

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.

PlaceboDRUG

Placebo to match ambrisentan was administered orally once daily.

SildenafilDRUG

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.

TadalafilDRUG

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.

Eligibility

Sex: ALLMin age: 16 YearsMax age: 75 Years

Medical Language ↔ Plain English

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 (30)

University of South Alabama

Mobile, Alabama, United States

Arizona Pulmonary Specialists

Phoenix, Arizona, United States

West Los Angeles Healthcare Center

Los Angeles, California, United States

Harbor - UCLA

Torrance, California, United States

Cleveland Clinic

Fort Lauderdale, Florida, United States

Outcomes

Primary Outcomes

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.

Time frame: Baseline to Week 24

Secondary Outcomes

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

This secondary hemodynamic outcome is supportive of the primary outcome. A decrease in measurement value (mmHg) indicates improvement for this patient population.

Time frame: Baseline to Week 24

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

This secondary hemodynamic outcome is supportive of the primary outcome. A decrease in measurement value (mmHg) indicates improvement for this patient population.

Time frame: Baseline to Week 24

Change From Baseline in Cardiac Output (LOCF)

This secondary hemodynamic outcome is supportive of the primary outcome. An increase in measurement value (L/min) indicates improvement for this patient population.

Time frame: Baseline to Week 24

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

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.