Inclusion Criteria:

Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.

1. Subject must be between 16 and 75 years of age, inclusive, at the Screening Visit
2. Subject must weigh greater than 40 kg at the Screening Visit

3. Subject must have a current diagnosis of IPAH, FPAH, or PAH that is primarily due to:

   • Connective tissue disease (e.g., limited scleroderma, diffuse scleroderma, mixed CTD, systemic lupus erythematosus, or overlap syndrome)

   • Congenital heart defects, including:

     • Congenital heart defects repaired greater than 1 year prior to screening (i.e., atrial septal defects, ventricular septal defects, and patent ductus arteriosus)
     • Unrepaired atrial septal defects, (only at selected sites following a qualification assessment, see Section 7.12.2)
   • Drug and toxin use
   • HIV infection
4. Subject must have WHO functional class III symptoms at the Screening Visit, as assessed by the Investigator
5. Subject must be receiving sildenafil (Revatio or Viagra) monotherapy for the treatment of PAH for greater than 12 weeks and at a stable dose of greater than 20 mg and less than 100 mg tid for at least 8 consecutive weeks prior to the Screening Visit

6. Subject must meet all of the following hemodynamic criteria by means of a RHC completed during the 3 weeks between the Screening and Randomization

   Visits (or at the Randomization Visit):

   • mPAP of greater than 25 mmHg
   • PVR greater than 400 dyne-sec/cm5
   • PCWP or LVEDP of ≤15 mmHg See Section 7.12 for details for determining and recording the hemodynamic parameters.

7. Subject must meet all of the following pulmonary function tests completed no more than 12 weeks before the Screening visit:

   • Total lung capacity (TLC) greater than 60% of predicted normal and
   • Forced expiratory volume in one second (FEV1) greater than 65% of predicted normal
8. Subject must walk a distance of at least 150 meters during the screening 6-minute walk test

9. Subject must meet all of the following hematology criteria:

   • A hemoglobin concentration greater than 10 g/dL at the Screening Visit
   • A hematocrit greater than 30% at the Screening Visit
10. Subjects, with or without supplemental oxygen, must have a resting arterial oxygen saturation (SaO2) greater than 90% as measured by pulse oximetry at the Screening Visit and have a SaO2 greater than 88% on room air during the RHC
11. Subject receiving CCBs or HMG-CoA reductase inhibitors (i.e., statins) must be on stable therapy for at least 4 weeks prior to the Screening Visit

12. Subject with a diagnosis of HIV must have stable disease status. For this study, stable HIV status is defined as:

    • No addition of medications for treatment of HIV for at least 8 weeks prior to screening
    • No active opportunistic infection during the Screening Period
    • No hospitalizations due to HIV for at least 4 weeks prior to screening
13. Female subject of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Randomization Visit. A female subject of childbearing potential is defined in Section 8.7.
14. Female subject of childbearing potential must agree to use 2 reliable methods of contraception from the Screening Visit until study completion and for at least 30 days following the last dose of study drug (reliable methods of contraception are described in Section 8.7)
15. Male subject must be informed of the potential risks of testicular tubular atrophy and infertility associated with taking this study drug and queried regarding his understanding of the potential risks as described in the Informed Consent Form (ICF)
16. Subject must agree not to participate in a clinical study involving another investigational drug or device throughout this study
17. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved ICF and must sign the form prior to the initiation of any study procedures

Exclusion Criteria:

Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:

1. Subject with a current PH diagnosis other than IPAH, FPAH, or PAH that is primarily due to:

   • Connective tissue disease (e.g., limited scleroderma, diffuse scleroderma, mixed CTD, systemic lupus erythematosus, or overlap syndrome)

   • Congenital heart defects, including

     • Congenital heart defects repaired greater than 1 year rior to screening (i.e., atrial septal defects, ventricular septal defects, and patent ductus arteriosus)
     • Unrepaired atrial septal defects (only at selected sites following a qualification assessment, see Section 7.12.2)
   • Drug and toxin use
   • HIV infection

   1.1. Subject with left ventricular ejection fraction (LVEF) less than 40% or clinically signification ischemic, valvular, or constrictive heart disease

2. Subject previously treated with ambrisentan in another clinical study or treated with commercial product (Letairis)
3. Subject has received chronic prostanoid or ERA therapy within the 12 weeks prior to the Screening Visit. Chronic prostanoid use is considered >7 days of treatment.
4. Subject received ERA treatment at any time and discontinued due to lack of efficacy, or safety/tolerance issues other than those associated with liver function test abnormalities
5. Subject receiving intravenous (iv) inotropes within 2 weeks prior to the Screening Visit
6. Subject has a serum ALT or AST lab value that is greater than 2.0xULN at the Screening Visit
7. Subject has a history of malignancies within the past 5 years, except for a subject with localized, non-metastatic basal cell carcinoma of the skin, in situ carcinoma of the cervix, or prostrate cancer who is not currently or expected, (during the study), to undergo radiation therapy, chemotherapy, hormonal treatment, and/or surgical intervention
8. Subject with cardiovascular, liver, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject and/or efficacy of the study drug or severely limit the lifespan of the subject
9. Female subject who is pregnant or breastfeeding
10. Subject has demonstrated noncompliance with previous medical regimens
11. Subject has a recent history of abusing alcohol or illicit drugs
12. Subject has participated in a clinical study involving another investigational drug or device within 12 weeks before the Screening Visit
13. Subject has a known hypersensitivity to the study drugs, the metabolites, or formulation excipients