Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 (NCT00423748) or AMB-321 (NCT00423202)
Brief Summary: AMB-320/321-E was designed to provide long-term, controlled monitoring of pulmonary arterial hypertension (PAH) patients treated with ambrisentan (AMB) in order to properly define the adverse event profile associated with this endothelin receptor antagonist (ERA), including the incidence and severity of elevated serum liver function tests (LFTs). In addition, this study continued the efficacy assessments of the previous studies, examined long-term AMB treatment success, and compared long-term survival of subjects treated with AMB to the NIH registry of patients with PAH.


Options:
A: Inclusion Criteria:

* Written informed consent
* Subject with CTEPH (WHO Group 4) judged as inoperable due to the localization of the obstruction being surgically inaccessible (i.e., distal disease).
* Female of childbearing potential must have a negative pre-treatment serum pregnancy test, be advised on appropriate methods of contraception, and agree to use 2 reliable methods of contraception.

Exclusion Criteria:

* Previous pulmonary endarterectomy.
* Recurrent thromboembolism despite sufficient oral anticoagulants.
* Symptomatic acute pulmonary embolism in the 6-month period prior to randomization.
* Known moderate-to-severe restrictive lung disease (i.e., TLC \< 60% of predicted value) or obstructive lung disease (i.e., FEV1 \< 70% of predicted, with FEV1/FVC \< 65%) or known significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung disease, emphysema).
* Acute or chronic conditions (other than dyspnea) that limit the ability to comply with study requirements in the 3-month period prior to Screening visit or during the Screening period.
B: Inclusion Criteria:

* Diagnosis of PAH of either primary (idiopathic), familial or secondary to systemic sclerosis (excluding those with marked pulmonary fibrosis) according to World Conference on Pulmonary Hypertension classification (Venice, 2003).
* Symptoms with a WHO class of II-IV

Exclusion Criteria:

* Use of unspecific phosphodiesterase inhibitors (for example, pentoxyfillin, enoximon, milrinone or pimobendan) during the study
* Chronic inhaled nitric oxide therapy from start to study completion
* Treatment with catecholamines (for example, adrenalin, noradrenalin, dopamine),
* Pre-existing lung diseases, including parasitic diseases affecting lungs, asthma, congenital abnormalities of the lungs, chest, and diaphragm.
* Pulmonary artery or valve stenosis; pulmonary venous hypertension; chronic thromboembolic pulmonary hypertension
* Acute heart failure or chronic left sided heart failure; congenital or acquired valvular or myocardial disease
* Severe (systemic) arterial hypertension (\> 200 mmHg (systolic) or \> 120 mmHg (diastolic)) Other protocol-defined inclusion/exclusion criteria may apply
C: Inclusion Criteria: Screening Criteria:

1. Males or females ≥ 12 years of age with a documented history of SCD
2. Patients with symptomatic PAH associated with shortness of breath
3. Patients with tricuspid regurgitation jet (TRJ) velocity of \> 2.9 m/sec based on echo/Doppler conducted within 6 months prior to randomization and not during SCD crisis
4. Signed written informed consent is obtained from the patient or patient's parent/legal representative prior to initiation of any study related procedure

Inclusion Criteria:

1. Patients with hemoglobin (Hb) SS or Hb S/β0 genotype and with Hb A ≤ 10%
2. Six-minute walk test (6MWT) distance ≥ 150 m and ≤ 450 m
3. PAH confirmed by right heart catheterization (RHC) performed at the study site within 3 months of the randomization visit and defined as:

   * Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg
   * Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg measured by RHC or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg measured by left heart catheterization, if PCWP measurement is not reliable
   * Pulmonary vascular resistance (PVR) at rest ≥ 160 dyn.sec/cm5
4. Women of childbearing potential must have a negative result on their serum pregnancy test and use reliable methods of contraception during study treatment and for 3 months after study treatment termination

Exclusion Criteria:

1. Left ventricular ejection fraction \< 40% (echo/Doppler)
2. Systolic blood pressure \< 85 mmHg
3. Uncontrolled hypertension with systolic blood pressure \>160 mmHg and/or diastolic blood pressure \> 100 mmHg
4. Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC) \< 0.5
5. Total lung capacity (TLC) \< 50% of normal predicted value
6. Significant cardiac disease: ischemic, valvular, constrictive
7. Hemoglobin concentration \< 6.0 g/dL at the time of randomization
8. Acute liver disease
9. Evidence of cirrhosis or portal hypertension on a liver ultrasound or biopsy
10. ALT ≥ 2 times upper limit of normal (ULN) and/or albumin \< 2.8 g/dL
11. Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements (in particular with 6MWT), e.g., angina pectoris, intermittent claudication, symptomatic hip osteonecrosis
12. Vaso-occlusive crisis (VOC) or acute chest syndrome (ACS) within 2 weeks of randomization or more than 12 VOC and/or ACS within the last 12 months
13. Blood transfusion within 4 weeks prior to randomization
14. Illness with a life expectancy shorter than 6 months
15. HIV with opportunistic infection
16. Psychotic, addictive, or other disorder limiting the ability to provide informed consent or to comply with study requirements
17. Pregnant or lactating women
18. Recently started (\< 8 weeks prior to randomization) or planned, exercise-based cardio-pulmonary rehabilitation program
19. Bone marrow transplantation
20. Treatment or planned treatment with another investigational drug within 3 months prior to randomization
21. Treatment for pulmonary hypertension with an endothelin receptor antagonist, a phosphodiesterase-5 inhibitor, prostanoids (excluding acute administration during a catheterization procedure to test vascular reactivity) within 3 months prior to randomization or with L-arginine within 1 week prior to randomization
22. Treatment with calcineurin-inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus, fluconazole, amiodarone, miconazole and glibenclamide (glyburide) within 1 week prior to randomization
23. Known hypersensitivity to bosentan or any of its excipients
D: Inclusion Criteria:

1. Subject must have completed Week 12 of AMB-320 (NCT00423748) or AMB-321 (NCT00423202) or must have received placebo during AMB-320 (NCT00423748) or AMB-321 (NCT00423202) and met two or more early escape criteria;
2. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form and must sign the form prior to the initiation of any study procedures.
3. Female subject of childbearing potential must agree to use two reliable methods of contraception until study completion and for at least four weeks following their final study visit. Reliable methods include: birth control pills/implants/injections, intrauterine devices (IUDs), spermicide, diaphragms, or condoms.

Exclusion Criteria:

* Subjects must have met the exclusion criteria of the AMB-320 (NCT00423748) and AMB-321 (NCT00423202)studies. In addition, a subject who meets any one of the following criteria is ineligible for participation in the study:

  1. Subject receiving bosentan, sildenafil, or iv inotropes at any time within four weeks prior to the AMB-320/321-E Screening/Randomization Visit;
  2. Subject receiving chronic prostanoid therapy (epoprostenol, treprostinil, iloprost, beraprost, or any other investigational prostacyclin derivative) within four weeks prior to the AMB-320/321-E Screening/RandomizationVisit;
  3. Female subject who is pregnant or breastfeeding;
  4. 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;
  5. Subject who has demonstrated noncompliance with previous medical regimens;
  6. Subject who has a recent history of abusing alcohol or illicit drugs;
  7. Subject who has participated in a clinical study involving another investigational drug or device at any time within four weeks prior to the AMB-320/321-E Screening/Randomization Visit.

Answer: D