Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension
Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension
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.
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.
Summarized Inclusion Criteria:

 1. 18 years of age or older

 2. 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).

 3. 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

 4. Right heart catheterization completed prior to screening must meet pre-specified
 criteria

 5. 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.

 6. 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:

 1. Participation in a previous clinical study with ambrisentan

 2. Bosentan or sitaxsentan use within four weeks prior to the screening visit

 3. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) lab value that is
 greater than 3 times the upper limit of normal at the screening visit

 4. 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

 5. Contraindication to treatment with endothelin receptor antagonist (ERA)

 6. History of malignancies other than basal cell carcinoma of the skin or in situ
 carcinoma of the cervix within the past five years

 7. Female participant who is pregnant or breastfeeding