Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized, Placebo-controlled, Double-blind, Multicenter, Parallel Group Study to Assess the Efficacy, Safety and Tolerability of Bosentan in Patients With Symptomatic Pulmonary Hypertension Associated With Sickle Cell Disease
Brief Summary: The study will assess the effect of bosentan on pulmonary vascular resistance and exercise capacity in Sickle Cell Disease (SCD) patients diagnosed with Pulmonary Hypertension. It consists of 3 phases: screening, treatment and follow-up. During the screening visit, the study doctor will decide if patients meet the study requirements. All potential patients will have a diagnosis of increased pulmonary artery pressures that is shown by right heart catheterization conducted shortly prior to start of study treatment. Patients will be asked to perform exercise capacity test (walking as far as possible for 6 minutes). Following the baseline visit the treatment phase consists of 4 additional clinic visits during which the good and bad effects of the drug are reviewed and exercise capacity test will be repeated. Patients will be treated for 16 weeks. Blood samples will be collected every month, or more often, if needed. At the end of the study some of the patients will be asked to repeat the right heart catheterization. All patients will repeat an exercise capacity test. After completion of the study, patients will have the option of enrolling in a long-term follow-up study where all patients will receive active drug. Patients electing not to participate in the extension study will be followed up for safety assessments for about 28 days after the end of the study treatment.


Options:
A: Inclusion Criteria:

* PAH NYHA Class II
* Significant elevation of mean pulmonary arterial pressure
* Significant elevation of pulmonary vascular resistance at rest
* Limited 6-minute walk distance

Exclusion Criteria:

* PAH secondary to portal hypertension, complex congenital heart disease or reverse shunt
* Restrictive or obstructive lung disease
* Significant vasoreactivity
* Treatments for PAH (within 4 weeks of randomization)
B: 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
C: Inclusion Criteria: Screening Criteria:

1. Males or females \> or = 12 years of age with a documented history of SCD
2. Patients with symptomatic PH 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 \< or = 10%
2. Six-minute walk test (6MWT) distance \> or = 150 m and \< or = 450 m
3. Pulmonary hypertension 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) \> or - 25 mmHg
   * Pulmonary capillary wedge pressure (PCWP) measured by right heart catheterization or left ventricular end diastolic pressure (LVEDP) measured by left heart catheterization, if PCWP measurement is not reliable. Two subsets of patients will be considered for this study:
   * PCWP \< or = 15 mm Hg, if PVR at rest \< 160 dyn.sec/cm5
   * PCWP of 16-25 mm Hg with any PVR value
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 (SBP) \< 85 mmHg
3. Uncontrolled hypertension with SBP \> 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. cirrhosis or portal hypertension
10. ALT \> or = 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. Signed informed consent prior to initiation of any study-mandated procedure
2. Males or females \>=12 years of age (except for countries where this age limit is contrary to specific regulatory requirements).

   - Women of childbearing potential must have a negative pretreatment pregnancy test and must use a reliable method of contraception during study treatment and for at least 3 months after study treatment termination.

   ·Reliable methods of contraception are:

   O Barrier type devices (e.g., female condom, diaphragm, contraceptive sponge) only in combination with a spermicide.

   O Intrauterine devices. O Oral, transdermal, injectable or implantable contraceptives only in combination with a barrier method.
   * Hormone-based contraceptives alone, regardless of the route of administration, are not considered as 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 postmenopausal (i.e., amenorrhea for at least 1 year), or documented surgically or naturally sterile.
3. Patients with symptomatic PAH
4. Patients with the following types of PAH belonging to WHO Group I:

   * Idiopathic (IPAH)
   * Familial (FPAH)
   * Associated with (APAH):

     i. Collagen vascular disease with normal left ventricular function (ejection fraction (EF) \> 50%) ii. Congenital systemic-to-pulmonary shunts at least 2 years post surgical repair iii. Drugs and toxins
5. PAH diagnosed by right heart catheter showing:

   * Mean pulmonary arterial pressure (mPAP) \>= 25 mm Hg AND
   * Pulmonary capillary wedge pressure (PCWP) =\< 15 mm Hg or left ventricular end diastolic pressure (LVEDP) =\< 15 mmHg If both PCWP and LVEDP are available then the LVEDP value is retained for inclusion.
6. Treatment with a stable dose of sildenafil equal to or greater than 20 mg t.i.d. for at least 12 weeks prior to randomization (no sildenafil dosage adjustment should occur in this period) 7)150 m =\< 6-minute walk test (6MWT) =\< 480 m, documented by 2 tests with second 6MWT within 15% of first 6MWT distance or a third test required

Exclusion Criteria :

1. PAH belonging to WHO group II-V
2. PAH associated with portal hypertension and HIV infection
3. PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy
4. PAH associated with significant venous or capillary involvement (PCWP \> 15 mmHg): pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
5. Persistent pulmonary hypertension of the newborn
6. Significant valvular disease with valvular lesions to be excluded by echocardiogram within 2 years prior to randomization (i.e. patients with tricuspid or pulmonary insufficiency secondary to PAH can be included)
7. Restrictive lung disease: total lung capacity (TLC) \< 60% of normal predicted value (see Appendix 3)
8. Obstructive lung disease: forced expiratory volume/forced vital capacity (FEV1/FVC) \< 0.5
9. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
10. Known HIV infection
11. Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements or that may interfere with the safety or the evaluation of the study, such as chronic infection, chronic renal failure etc.
12. Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements
13. Pregnancy or breast-feeding
14. Condition that prevents compliance with the protocol or adherence to therapy
15. Systolic blood pressure \< 85 mmHg
16. Body weight \< 40 kg
17. Hemoglobin \<75% of the lower limit of the normal range
18. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 1.5 times the upper limit of normal ranges
19. Known hypersensitivity or history of drug-related adverse events with bosentan (e.g. increase in liver function test results), or any of the excipients of its formulation
20. Receipt of an investigational product other than sildenafil within 3 months before start of study treatment
21. Treatment with endothelin receptor antagonists (ERAs), prostanoids or phosphodiesterase (PDE) 5 inhibitors other than sildenafil within 3 months prior to randomization
22. Concomitant systemic treatment within 1 week prior to randomization with

    * calcineurin inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus and everolimus
    * glibenclamide (glyburide)
    * both cytochrome P2C9 (CYP2C9) and cytochrome P3A4 (CYP3A4) (e.g., fluconazole, amiodarone, voriconazole)
    * combination of drugs that inhibit CYP2C9 and CYP3A4
23. Treatment with nitrates and alpha-blockers at time of randomization
24. In the opinion of the investigator - patients in need for treatment with any prostanoid up to Visit 4
25. Significant left ventricular dysfunction

Answer: C