Please select the eligibility criteria that correspond to the clinical trial below.
Title: Long-Term, Open-Label, Multicenter, Extension Study of Bosentan in Patients With Pulmonary Hypertension Associated With Sickle Cell Disease Completing a Double-Blind ASSET Study (AC-052-368 or AC 052-369)
Brief Summary: This study will assess the safety and efficacy of bosentan therapy (in a study known as ASSET) for patients who have high blood pressure in the lungs associated with sickle cell disease. That form of hypertension places people at risk for complications, including shortness of breath, pain, pneumonia, and death. Previous studies have shown that bosentan can be helpful in reducing pulmonary hypertension.

Patients ages 16 and older who have completed the 16-week treatment in the ASSET 1 or ASSET 2 study and who are not pregnant or breastfeeding may be eligible for this study. The research will be conducted in about 25 hospitals in the United States and Europe. Up to 30 participants will be enrolled. The screening visit will involve a physical examination, blood sample of about 3 teaspoons for laboratory tests, and a pregnancy test. Patients' doctors will give them bosentan tablets (62.5 mg each), to take one in the morning and one in the evening. After 1 month, patients will be told whether the dose should be increased to 125 mg tablets to take twice a day. Two weeks after the increase in dose, a blood test will be done to analyze the drug's effects on the liver. After the start of treatment, patients will return for visits every 6 months, when there will be a 6-minute walking test to measure exercise capacity and evaluate shortness of breath. There will be follow-up for patients up to the end of the study and for 28 days after the last dose of bosentan is taken, to collect information about side effects.

Some patients on bosentan have had changes in liver function and red blood cell count. Side effects commonly reported are headache, flushed appearance, inflammation of the throat and nasal passages, and gastrointestinal symptoms. If patients have sudden worsening in breathing in the first few weeks after taking bosentan, they should immediately tell their doctors, because it may be necessary to change the treatment.


Options:
A: Inclusion Criteria:

* Symptomatic pulmonary hypertension in modified NYHA functional class II to IV due to CTEPH as demonstrated by ventilation/perfusion lung scanning and pulmonary angiography.
* CTEPH judged inoperable because of peripheral localization of thrombotic material or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (PEA) with no evidence of recurrent thromboembolism and not amenable to repeated surgery.
* 6-minute walk test (6MWT) distance \< 450 m.
* Hemodynamic evaluation showing: Mean pulmonary arterial pressure (mPAP) \>= 25 mmHg; Pulmonary capillary wedge pressure (PCWP) \< 15 mmHg; Pulmonary vascular resistance (PVR) at rest \>= 300 dyn×sec/cm5
* For patients who underwent PEA, hemodynamic evaluation must have been performed more than 6 months after PEA.
* For all patients, hemodynamic evaluation must have been performed with the 3 months immediately preceding inclusion.
* Men or women \>= 18 and =\< 80 years of age (Women of childbearing potential must have a negative pre-treatment pregnancy test and use a reliable method of contraception).
* Anticoagulants at efficacious dose for at least 3 months prior to randomization.
* Signed informed consent prior to initiation of any study-mandated procedure.

Exclusion Criteria:

* Other forms of pulmonary hypertension including pulmonary hypertension related to sickle cell disease.
* Obstructive lung disease: FEV1/FVC \< 0.5 after bronchodilator.
* Severe restrictive lung disease: Total Lung Capacity \< 60% of predicted value.
* 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 pulmonary embolism within 6 months prior to randomization.
* Pulmonary endarterectomy within 6 months prior to randomization.
* Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements.
* Illness with a life expectancy of less than 6 months.
* Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
* AST and/or ALT \> 3 times the upper limit of normal ranges.· Hemoglobin concentration \< 75% the lower limit of normal ranges.
* Pregnancy or breast-feeding.
* Systolic blood pressure (BP) \< 85 mmHg.
* Treatment or planned treatment with another investigational drug and/or pulmonary angioplasty within 3 months prior to randomization.
* Treatment with an endothelin receptor antagonist, a phosphodiesterase inhibitor, L-arginine or with prostanoids (excluding acute administration during a catheterization procedure to test vascular reactivity) within 3 months prior to randomization.
* Treatment for pulmonary hypertension within 1 month prior to randomization, excluding calcium channel blockers if present for at least 1 month before randomization.
* Treatment with calcineurin-inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus, fluconazole, glibenclamide (glyburide) within 1 week prior to randomization.
* Known hypersensitivity to bosentan or any of the excipients.
B: 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.
C: * INCLUSION CRITERIA
* Completion of the 16-week treatment period in the double-blind ASSET study
* 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.

Reliable methods of contraception are:

1. Barrier type devices (e.g., female condom, diaphragm, contraceptive sponge) only in combination with a spermicide.
2. Intra-uterine devices.
3. Oral, injectable, transdermal or implantable contraceptives only in combination with a barrier method.

Hormone-based contraceptives alone, regardless of the route of administration, are not considered to be reliable methods of contraception.

Abstention, rhythm method, and contraception by the partner alone are not acceptable methods of contraception.

Women not of childbearing potential are defined as prepubescent, postmenopausal (i.e., amenorrhea for at least 1 year), or surgically or naturally sterile.

Signed written informed consent is obtained from the patient or patient's parent/ legal representative prior to initiation of any study-related procedure.

EXCLUSION CRITERIA

All patients (Groups A and B):

1. Any major protocol violation in the preceding double-blind ASSET study\*.
2. Hemoglobin concentration less than 6.0 g/dL.
3. Pregnancy or breast-feeding.

   \* Protocol violations will be reviewed by the monitor during site visits and discussed with the study staff on an ongoing basis and at the patient's completion of the double-blind study.

   Group B only:
4. Acute liver disease.
5. Newly diagnosed cirrhosis or portal hypertension.
6. ALT greater than or equal to 3 times ULN and/or albumin greater than 20% below LLN.
7. Newly diagnosed psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements.
D: 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.

Answer: C