Please select the eligibility criteria that correspond to the clinical trial below.
Title: ARIES 1 and ARIES 2: Ambrisentan in PAH - A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter, Efficacy Study of Ambrisentan in Subjects With Pulmonary Arterial Hypertension
Brief Summary: The primary objective is to determine the effect of ambrisentan on exercise capacity in subjects with PAH.


Options:
A: Inclusion Criteria:

1. Male or female patients over 18 years of age.

   * Women must be either postmenopausal (i.e., amenorrhea for at least 1 year), or surgically or naturally sterile.
   * Women of childbearing potential must have a negative pre-treatment pregnancy test and use a reliable method of contraception during study treatment and for at least 3 months after study treatment termination.
2. IPF proven diagnosis \< 3 years documented according to ATS/ERS international multidisciplinary consensus, with or without surgical (thoracoscopic or open) chest lung biopsy
3. Duration of illness ≥ 3 months.
4. Six-minute walk test distance (limited by dyspnea) ≥ 150 meters and \< 500 meters
5. Patients who have signed the informed consent form prior to initiation of any study procedure.

Exclusion Criteria:

1. Interstitial lung disease due to conditions other than IPF, including but not limited to radiation, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans with organizing pneumonia, and cancer.
2. History of clinically significant environmental exposure known to cause pulmonary fibrosis (drugs, asbestos, beryllium, radiation, domestic birds, etc.).
3. Severe concomitant illness limiting life expectancy (\< 1 year).
4. FVC ≥ 90% predicted.
5. Severe restrictive lung disease: FVC \< 50% predicted or FVC \< 1.2 l, or DLco \< 30% predicted or residual volume ≥ 120% predicted.
6. Severe obstructive lung disease: FEV1/FVC\< 0.65.
7. Documented improvement of patient's condition within 12 months prior to randomization with or without IPF-specific therapy (e.g., corticosteroids, immunosuppressive, cytotoxic or antifibrotic drugs, TNFa blocker, interferon g).
8. Recent pulmonary or upper respiratory track infection (within 4 weeks of randomization).
9. PaO2 \< 55 mm Hg (sea level) or 50 mm Hg (altitude) at rest on room air.
10. Echocardiographic evidence of severe pulmonary hypertension (PH): systolic pulmonary pressure ≥ 50 mm Hg or tricuspid regurgitation velocity ≥ 3.2 m/sec (unless severe PH is invalidated by a right heart catheterization). If the pulmonary pressure is not quantifiable, presence of significant right ventricular enlargement or hypertrophy or right ventricular dysfunction.
11. Severe chronic heart failure, e.g., NYHA class III or IV and/or left ventricular ejection fraction \< 25%.
12. Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements, e.g., the 6MWT or the PFTs.

    (e.g., angina pectoris, intermittent claudicating, chronic arthritis).
13. Baseline values of liver transaminases, i.e., aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT) \> 3 times the upper limit of normal ranges.
14. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
15. Serum creatinine ≥ 2.5 mg/dl (221 mmol/l) or dialysis.
16. Hemoglobin concentration \< 75% the lower limit of normal ranges.
17. Systolic blood pressure \< 85 mm Hg.
18. Pregnancy or breast-feeding.
19. Current drug or alcohol dependence.
20. Smoker (≥ 5 cigarettes per day) or former smoker (≥ 5 cigarettes per day) having stopped less than 6 months prior to randomization.
21. Recently started (\< 8 weeks from Screening visit) or planned cardio-pulmonary rehabilitation program based on exercise.
22. Treatment with oral corticosteroids (\> 15 mg/day prednisone or equivalent), immunosuppressive, cytotoxic or antifibrotic drugs such as TNF alpha blocker, or interferon gamma within 4 weeks of randomization.within 4 weeks of randomization.
23. Treatment with glibenclamide (glyburide), cyclosporine A or tacrolimus within 1 weeks of randomization.
24. Treatment with an endothelin receptor antagonist within 3 months of randomization.
25. Treatment within 3 months of randomization or planned treatment with another investigational drug.
26. Known hypersensitivity to bosentan or any of the excipients.
B: Inclusion Criteria:

* At least 12 years of age.
* Body weight at least 40 kg (approximately 88 pounds).
* Pulmonary hypertension (PAH) that is either idiopathic; related to collagen vascular disease; related to anorexigen use; associated with an atrial septal defect (resting SaO2 greater than or equal to 88%); with surgical repair, of at least 1 year duration, of a congenital systemic-to-pulmonary shunt.
* If on bosentan, must be at the maximal dose of 125 mg twice daily for a minimum of 12 weeks prior to screening and have an AST/ALT less than 3 times normal.
* History of PAH established by a resting mean pulmonary artery pressure greater than or equal to 25 mm Hg, pulmonary artery wedge pressure less than or equal to 15 mm Hg, and pulmonary vascular resistance greater than or equal to 3 Wood units via right heart catheterization
* Have World Health Organization functional class I, II, III or IV status.
* Have a qualifying 6-minute walk test distance at screening
* Have no evidence of significant parenchymal lung disease

Exclusion Criteria:

* Are nursing or pregnant.
* PAH due to conditions other than noted in the above inclusion criteria.
* History of left-sided heart disease.
* History of atrial septostomy within 3 months before study entry
* History of angina pectoris or other condition that was treated with long-or short-acting nitrates within 12 weeks before administration of study drug.
* History of symptomatic coronary disease.
* Have any therapy with a prostacyclin or analogue, L-arginine, phosphodiesterase (PDE) inhibitor, or investigational drug within 4 weeks before administration of study drug.
C: Inclusion Criteria:

* Diagnosis of idiopathic PAH (formally known as PPH), or PAH associated with collagen vascular disease, anorexigen use, or HIV infection;
* Historical cardiac catheterization with the following hemodynamic criteria:

Mean pulmonary artery pressure greater than or equal to 25 mmHg; Pulmonary vascular resistance greater than 3 mmHg/L/min; Pulmonary capillary wedge pressure or left ventricular end diastolic pressure less than 15 mmHg;

* 6-minute walk distance of at least 150 meters, but no more than 450 meters;
* Total lung capacity greater than or equal to 70% and FEV1 greater than or equal to 65% of predicted normal;

Exclusion Criteria:

* Portopulmonary hypertension;
* Subjects with PAH due to or associated with coronary artery disease, left heart disease, interstitial lung disease, chronic obstructive pulmonary disease, veno-occlusive disease, chronic thromboembolic disease, or sleep apnea;
* Bosentan (Tracleer®), sildenafil (Viagra®), or chronic prostanoid therapy within 4 weeks of screening;
* Serum ALT or AST lab value that is greater than 1.5 times the upper limit of normal;
* Contraindication to treatment with an endothelin receptor antagonist;
* Subject with cardiovascular, hepatic, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that may adversely affect the safety of the subject;
* Participation in a clinical study involving another investigational drug within 4 weeks of screening.
D: Inclusion Criteria:

1. Male or female patients 18 years of age or older
2. Histologically proven malignant melanoma (Balch et al., J. Clin Oncol. 19(16): 3635-48, 2001) with stage IV measurable disease as defined by RECIST criteria (Therasse et al., J Natl Cancer Inst, 92(3): 205-16, 2000).
3. Patients with prior radiation therapy (\> 30 days prior to study drug initiation) will be allowed provided the indicator lesion(s) used for this study was (were) outside the field of radiation or represent new lesions not previously irradiated.
4. Patients who had no prior therapy with DTIC.
5. Patients with cutaneous melanoma lesions must consent to having a biopsy obtained during the screening period and at the end of treatment for exploratory analysis of endothelin receptor expression. Biopsies obtained prior to the study that have been frozen in accordance with procedures specified for this protocol may be used.
6. ECOG performance status (≤ 2)
7. Life expectancy \> 12 weeks
8. Female patients must be non-pregnant, non-breast feeding, and either post menopausal, surgically sterile, or practicing a reliable method of contraception (hormonal methods alone are not sufficient)
9. Provide written informed consent
10. Willing to return to study center for follow up

Exclusion Criteria:

1. ALT and/or AST \> 3 × the upper limit of normal (ULN) at screening OR ALT and /or AST \> 2 x ULN and total bilirubin \> 2.0 mg/dl at screening
2. Lactate dehydrogenase \> 1.5 x ULN
3. Hemoglobin \>30% below the lower limit of normal
4. Systolic blood pressure \< 85 mmHg
5. NYHA class III/IV congestive heart failure
6. Any prior chemotherapy, biological therapy or immunotherapy for stage IV metastatic disease.
7. Received immunotherapy \< 30 days before treatment start (completed adjuvant immunotherapy for previous resected metastatic disease is allowed)
8. Concurrent use of calcineurin inhibitors (cyclosporine A, tacrolimus), sirolimus, fluconazole or glibenclamide (glyburide) or expected to receive any of these drugs during the study at inclusion and during the study.
9. History of other malignancy in the last 5 years, with the exception of squamous cell carcinoma of the skin treated with local resection and basal cell carcinoma
10. CNS metastases or carcinomatous meningitis
11. Ocular melanoma
12. Known hypersensitivity to any excipients of Tracleer™
13. Prior therapy with bosentan
14. Use of therapy with another investigational drug within 4 weeks of the start of dosing with bosentan or plan to receive such treatment during the study
15. Known drug or alcohol dependence or any other factor that will interfere with the conduct of the study
16. Any standard contraindications for the use of DTIC as per Australian package insert

Answer: C