Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Assess the Efficacy, Safety and Tolerability of Bosentan in Patients With Interstitial Lung Disease Associated With Systemic Sclerosis
Brief Summary: Clinical and experimental studies suggest that bosentan could delay the progression of interstitial lung disease (ILD) associated with systemic sclerosis (SSc), a condition for which no established efficacious treatment is available. The present trial investigates a possible use of oral bosentan, which is currently approved for the treatment of symptoms of pulmonary arterial hypertension (PAH) WHO Class III and IV, to a new category of patients suffering from ILD associated with SSc.


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: 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: Main inclusion criteria:

* Systemic Sclerosis diffuse or limited
* Significant Interstitial Lung Disease on HRCTscan
* DLco \< 80% predicted
* Dyspnea on exertion
* Walk not limited by musculoskeletal reasons

Main exclusion criteria:

* Interstitial Lung Disease due to other conditions than SSc
* End stage restrictive or obstructive lung disease
* Severe cardiac or renal diseases
* Significant pulmonary arterial hypertension
* Smoker (\> 5cig./day)
* Treatment with immunosuppressive, antifibrotic drugs, high dose corticosteroids (within 4 weeks of randomization)
D: 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.

Answer: C