Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Assess the Efficacy, Safety, and Tolerability of Bosentan in Patients With Mildly Symptomatic Pulmonary Arterial Hypertension (PAH)
Brief Summary: The present trial investigates a possible use of oral bosentan, which is currently approved for the treatment of symptoms of pulmonary arterial hypertension (PAH) Class III and IV, to patients suffering from PAH Class II.


Options:
A: 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
B: Inclusion Criteria:

* Clinically stable, pulmonary arterial hypertension diagnosed as either idiopathic or familial PAH, collagen vascular disease associated PAH, HIV PAH, or PAH induced by anorexigens, New York Heart Association (NYHA) Class III or Class IV.
* Been on a stable dose of 125 mg twice daily (bid) of bosentan OR any stable dose of sildenafil for at least three months prior to study start
* An unencouraged six minute walk test (6MWT) of between 200 and 450 meters at screening
* Cardiac catheterization within the past 13 months consistent with PAH, specifically mean pulmonary artery pressure (PAPm) ≥25 mmHg (at rest), pulmonary capillary wedge pressure (PCWP) (or left ventricular end diastolic pressure) ≤15 mmHg, and pulmonary vascular resistance (PVR) \>3 mmHg/L/min
* Within the past 12 months, patients must have had a chest radiograph consistent with the diagnosis of PAH
* Willing and able to follow all study procedures

Exclusion Criteria:

* Considering pregnancy, are pregnant and/or lactating
* PAH due to conditions other than noted in the above inclusion criteria.
* Have had any change in or discontinued any PAH medication within the last three months, including but not limited to endothelin receptor antagonist (ERA), or calcium channel blockers (CCB) (with the exception of anticoagulants)
* Have received any prostanoid within the 30 days before screening or are scheduled to receive any during the course of the study
* Have received any investigational medication within 30 days prior to the start of this study or are scheduled to receive another investigational drug during the course of this study
* Have a known intolerance to any drug, especially to treprostinil sodium or prostanoids
* Have an increased risk of hemorrhage
* Have a new type of chronic therapy (e.g., a different category of vasodilator, diuretic) for PAH added within the last month, except anticoagulants
* Have any musculoskeletal disease or any other disease that would limit ambulation.
C: 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)
D: 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.

Answer: C