Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension

Study Overview
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Brief Summary
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The primary objective of this study was to evaluate the safety and efficacy of ambrisentan in a broad population of participants with pulmonary hypertension (PH). Secondary objectives of this study were to evaluate the effects of ambrisentan on other clinical measures of pulmonary arterial hypertension (PAH), long-term treatment success, and survival.

Detailed Description
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This study was to enroll up to 200 participants with PH due to the following etiologies: 1) PAH including idiopathic and familial PAH and PAH associated with collagen vascular disease, congenital systemic-to-pulmonary shunts (including Eisenmenger's syndrome), human immunodeficiency virus (HIV) infection, drugs and toxins, thyroid disorders, glycogen storage disease, Gaucher disease, hemoglobinopathies, and splenectomy (WHO Group 1); 2) PH associated with lung diseases and/or hypoxemia, including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), sleep-disordered breathing, and alveolar hypoventilation disorders (WHO Group 3); 3) PH due to proximal or distal chronic thromboembolic obstruction (WHO Group 4); and 4) PH due to sarcoidosis (WHO Group 5). Participants with left heart disease or left heart failure were excluded (WHO Group 2). Participants could be receiving prostacyclin or sildenafil therapy at baseline, and participants who previously discontinued either bosentan, sitaxsentan, or both, due to liver function test abnormalities were eligible.

Official Title
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ARIES-3: A Phase 3, Long-Term, Open-Label, Multicenter Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension

Conditions
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Pulmonary Hypertension

Intervention / Treatment
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* Drug: Ambrisentan


Participation Criteria
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Eligibility Criteria
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Summarized Inclusion Criteria: 18 years of age or older Current diagnosis of PH associated with an acceptable etiology as outlined in the protocol, including: PH due to the following etiologies: 1) PAH including idiopathic and familial PAH and PAH associated with collagen vascular disease, congenital systemic-to-pulmonary shunts (including Eisenmenger's syndrome), human immunodeficiency virus (HIV) infection, drugs and toxins, thyroid disorders, glycogen storage disease, Gaucher disease, hemoglobinopathies, and splenectomy (WHO Group 1); 2) PH associated with lung diseases and/or hypoxemia, including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), sleep-disordered breathing, and alveolar hypoventilation disorders (WHO Group 3); 3) PH due to proximal or distal chronic thromboembolic obstruction (WHO Group 4); and 4) PH due to sarcoidosis (WHO Group 5). Stable regimen (within four weeks) of chronic prostanoid, PDE-5 inhibitor, calcium channel blocker, or 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor therapy Right heart catheterization completed prior to screening must meet pre-specified criteria Female participants of childbearing potential must have a negative serum pregnancy test and must agree to use a reliable double method of contraception until study completion and for at least four weeks following their final study visit. Male participants must be informed of the potential risks of testicular tubular atrophy and infertility associated with taking ambrisentan and queried regarding his understanding of the potential risks as described in the Informed Consent Form. Summarized Exclusion Criteria: Participation in a previous clinical study with ambrisentan Bosentan or sitaxsentan use within four weeks prior to the screening visit Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) lab value that is greater than 3 times the upper limit of normal at the screening visit Pulmonary function tests not meeting the following pre-specified criteria: 1) mean pulmonary arterial pressure (PAP) >= 25 mm Hg; 2) PVR > 3 mm Hg/L/min; 3) pulmonary capillary wedge pressure (PCWP) or left ventricle end diastolic pressure (LVEDP) < 15 mm Hg; 4) total lung capacity (TLC) >= 70% of predicted normal for participants without ILD or >= 60% of predicted normal in participants with ILD; forced expiratory volume in 1 second (FEV1) >= 65% of predicted normal in participants without COPD or >= 50% of predicted normal in participants with COPD Contraindication to treatment with endothelin receptor antagonist (ERA) History of malignancies other than basal cell carcinoma of the skin or in situ carcinoma of the cervix within the past five years Female participant who is pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ambrisentan<br> | Drug: Ambrisentan<br>* Oral tablets taken once daily.<br>* Other names: Volibris;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in 6 Minute Walk Distance (6MWD) |  | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in Borg Dyspnea Index | Change from Baseline to Week 24 in Borg Dyspnea Index. The Borg Dyspnea Index of Perceived Exertion Scores range from 0 to 10. Best and Worst values are: 0 (Best) to 10 (Worst). Scales are described as rating of breathlessness and its description: 0= none; 0.5= very,very slight (just noticeable); 1= very slight; 2=slight; 3= moderate; 4= somewhat severe; 5= severe; 6 (in between severe and very severe); 7= very severe; 8 (in between very, very severe and maximum); 9= very, very severe; and 10= maximum. | Baseline to Week 24 | 
| Change From Baseline to Week 48 in Borg Dyspnea Index | Change from Baseline to Week 48 in Borg Dyspnea Index. The Borg Dyspnea Index of Perceived Exertion Scores range from 0 to 10. Best and Worst values are: 0 (Best) to 10 (Worst). Scales are described as rating of breathlessness and its description: 0= none; 0.5= very,very slight (just noticeable); 1= very slight; 2=slight; 3= moderate; 4= somewhat severe; 5= severe; 6 (in between severe and very severe); 7= very severe; 8 (in between very, very severe and maximum); 9= very, very severe; and 10= maximum. | Baseline to Week 48 | 
| Percent Change From Baseline to Week 24 in B-type Natriuretic Peptide (BNP) |  | Baseline to Week 24 | 
| Percent Change From Baseline to Week 48 in BNP |  | Baseline to Week 48 | 
| Change From Baseline to Week 24 in WHO Functional Class | Change from baseline in World Health Organization functional class (WHO) at Week 24 is the incidence of participants that improved, had no change, or worsened. WHO categories are 1 to 4 with the worse category at 4. Improvement = a category change from baseline of <= -1: change of -3 (eg, WHO from 4 to 1), change of -2 (eg, WHO from 3 to 1), change of -1 (eg, WHO from 2 to 1). Inversely, participants worsening are those with a category change from baseline of at least +1. No change in WHO functional class represents the percentage of participants with a change in category from baseline of 0. | Baseline to Week 24 | 
| Change From Baseline to Week 48 in WHO Functional Class | Change from baseline in WHO at Week 48 is expressed as the incidence of participants that improved, had no change or worsened. WHO categories range from 1 to 4 with the worse category at 4. Improvement = a category change from baseline of <= -1: change of -3 (eg, WHO from 4 to 1), change of -2 (eg, WHO from 3 to 1), change of -1 (eg, WHO from 2 to 1). Inversely, participants worsening are those with a category change from baseline of at least +1. No change in WHO functional class represents the percentage of participants with a change in category from baseline of 0. | Baseline to Week 48 | 
| Change From Baseline to Week 24 in SF-36 Health Survey Physical Functioning Scale | Change from baseline to Week 24 in the SF-36 health survey physical functioning scale. 10 activities rated by health limitations using 3 categories (1= Yes, limited a lot; 2= Yes, limited a little; and 3= No, not limited at all). The best score is 3 and the worst score is 1. Scores are transformed by subtracting the unit by the lowest raw score and dividing by the raw score range. The scores are then standardized with the 1998 General United States (US) population mean and standard deviation (SD). Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10. | Baseline to Week 24 | 
| Change From Baseline to Week 48 in SF-36 Health Survey Physical Functioning Scale | Change from baseline to Week 48 in the SF-36 health survey physical functioning scale. 10 activities are rated by health limitations using 3 categories (1= Yes, limited a lot; 2= Yes, limited a little; and 3= No, not limited at all). The best score is 3 and the worst score is 1. Scores are transformed by subtracting the unit by the lowest raw score and dividing by the raw score range. The scores are then standardized with the 1998 General US population mean and standard deviation. Finally, the scores are transformed to the norm-based scoring with a mean of 50 and standard deviation of 10. | Baseline to Week 48 | 
| Percent of Participants With no Clinical Worsening of Pulmonary Hypertension (PH) at Week 24 | Clinical worsening: occurrence of death, lung transplantation, hospitalization for PH, atrial septostomy, a change to chronic prostanoid or sildenafil treatment due to protocol-defined worsening criteria, or study withdrawal due to the addition of other clinically approved PH therapeutic agents | Baseline to Week 24 | 
| Percent of Participants With no Clinical Worsening of PH at Week 48 | Clinical worsening: occurrence of death, lung transplantation, hospitalization for PH, atrial septostomy, a change to chronic prostanoid or sildenafil treatment due to protocol-defined worsening criteria, or study withdrawal due to the addition of other clinically approved PH therapeutic agents | Baseline to Week 48 | 
| Failure-free Treatment Status | Defined by occurrence of death, lung transplantation, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents | Baseline to Week 24 | 
| Failure-free Treatment Status | Defined by occurrence of death, lung transplantation, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents | Baseline to Week 48 | 
| Monotherapy Treatment Status | Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment | Baseline to Week 24 | 
| Monotherapy Treatment Status | Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment | Baseline to Week 48 | 
| Long-term Survival | Defined as not dying during study participation | Baseline to Week 24 | 
| Long-term Survival | Defined as not dying during study participation | Baseline to Week 48 |