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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Ambrisentan
* Drug: Placebo
* Drug: Sildenafil
* Drug: Tadalafil


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ambrisentan<br>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<br>* 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.<br>* Other names: Letairis;Drug: Sildenafil<br>* 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.<br>* Other names: Viagra;Drug: Tadalafil<br>* 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.<br>* Other names: Adcirca;|
| Active Comparator: Placebo<br>Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (sildenafil or tadalafil). | Drug: Placebo<br>* Placebo to match ambrisentan was administered orally once daily.<br>Drug: Sildenafil<br>* 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.<br>* Other names: Viagra;Drug: Tadalafil<br>* 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.<br>* Other names: Adcirca;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | Baseline to Week 48 | 
| Change in Dyspnea Index 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. 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. | Baseline to Week 48 | 
| 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) | 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. | Baseline to Week 48 | 
| Change From Baseline in World Health Organization (WHO) Functional Class (LOCF) Measured at Weeks 4, 12, 24, 36 and 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). | Baseline to Week 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) | 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. | Baseline to Week 48 | 
| 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 | 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. | Baseline to Week 48+ | 
| Overall Survival, Evaluated at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and After 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. | Baseline to Week 48+ | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ambrisentan, PAH, combination therapy, phosphodiesterase type-5 inhibitor (PDE-5i), cardiovascular, endothelin receptor antagonist, ERA