Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group, Event-driven, Phase III Study to Assess the Effects of Macitentan (ACT-064992) on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension
Brief Summary: The AC-055-302/SERAPHIN study will be an event-driven Phase III study, comparing two different doses of macitentan (ACT-064992) (3 and 10 mg) vs placebo in patients with symptomatic PAH. The main study objective is to demonstrate that macitentan (ACT-064992) prolongs time to the first morbidity or mortality event, and to evaluate the benefit/risk profile of macitentan (ACT-064992) in the treatment of patients with symptomatic PAH.


Options:
A: Inclusion Criteria:

* Diagnosis of PAH of either primary (idiopathic), familial or secondary to systemic sclerosis (excluding those with marked pulmonary fibrosis) according to World Conference on Pulmonary Hypertension classification (Venice, 2003).
* Symptoms with a WHO class of II-IV

Exclusion Criteria:

* Use of unspecific phosphodiesterase inhibitors (for example, pentoxyfillin, enoximon, milrinone or pimobendan) during the study
* Chronic inhaled nitric oxide therapy from start to study completion
* Treatment with catecholamines (for example, adrenalin, noradrenalin, dopamine),
* Pre-existing lung diseases, including parasitic diseases affecting lungs, asthma, congenital abnormalities of the lungs, chest, and diaphragm.
* Pulmonary artery or valve stenosis; pulmonary venous hypertension; chronic thromboembolic pulmonary hypertension
* Acute heart failure or chronic left sided heart failure; congenital or acquired valvular or myocardial disease
* Severe (systemic) arterial hypertension (\> 200 mmHg (systolic) or \> 120 mmHg (diastolic)) Other protocol-defined inclusion/exclusion criteria may apply
B: Inclusion Criteria:

* aged 10 to 80
* treatment naive symptomatic PAH
* 6-MWD of 100-425 m
* resting mean pulmonary artery pressure greater than 25 mm Hg, pulmonary capillary wedge pressure less than 15 mm Hg, and pulmonary vascular resistance of 240 dyn.s.cm-5 or greater.

Exclusion Criteria:

* Patients with thromboembolic disease,
* untreated obstructive sleep apnea,
* portal hypertension,
* chronic liver disease or renal insufficiency,
* left-sided or unrepaired congenital heart disease,
* substantial obstructive (FEV1/FVC\<50% predicted) or restrictive (total lung capacity\<60% predicted) lung disease
* Patients receiving phosphodiesterase inhibitors or other prostanoids and endothelin receptor antagonists
C: Inclusion Criteria:

* Eisenmenger syndrome
* Negative pregnancy test

Exclusion Criteria:

* Elevated liver enzymes to more than 3´times normal value
* Hypotension (SBP \< 90 mmhg).
* Mandatory treatment with nitrates
* Myocardial infarction within 3 months
* Stroke within 3 months
* Known allergy to Bosentan or Sildenafil
* inherited degenerative diseases in retina
* Breast feeding
* Suspicion of risc of noncompliance.
D: Inclusion Criteria:

1. Signed informed consent prior to initiation of any study mandated procedure.
2. Patients with symptomatic pulmonary arterial hypertension (PAH) in modified World Health Organization (WHO) functional class II to IV.
3. Patients with the following types of pulmonary arterial hypertension (PAH) belonging to groups 1.1 to 1.3 of the Venice classification:

   * Idiopathic (IPAH);
   * Familial (FPAH); or
   * Related to:

     * Collagen vascular disease;
     * Simple, congenital systemic-to-pulmonary shunts at least 1 year post surgical repair;
     * Human immunodeficiency virus (HIV) infection; or
     * Drugs and toxins.
4. PAH diagnosis confirmed by hemodynamic evaluation performed prior to randomization and showing all of the following:

   * Mean pulmonary artery pressure (mPAP) \> 25 mmHg at rest;
   * Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) \< 15 mmHg; and
   * Pulmonary vascular resistance (PVR) at rest \>= 320 dyn×sec/cm\^5.
5. 6-minute walk distance (6MWD) \>= 50 m.
6. Men or women \> 12 years of age (women of childbearing potential must have a negative pre-treatment serum pregnancy test and must use a reliable method of contraception).

Exclusion Criteria:

1. PAH associated with portal hypertension, thyroid disorders, glycogen storage disease, Gaucher''s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy.
2. PAH associated with non corrected simple congenital systemic-to-pulmonary shunts, and combined and complex systemic-to-pulmonary shunts, corrected or non corrected.
3. PAH associated with significant venous or capillary involvement (PCWP \> 15 mmHg), known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis.
4. Persistent pulmonary hypertension of the newborn.
5. Pulmonary Hypertension belonging to groups 2 to 5 of the Venice classification.
6. Moderate to severe obstructive lung disease: forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) \< 70% and FEV1 \< 65% of predicted value after bronchodilator administration.
7. Moderate to severe restrictive lung disease: total lung capacity (TLC) \< 60% of predicted value.
8. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
9. Estimated creatinine clearance \< 30 mL/min
10. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 1.5 times the upper limit of normal.
11. Hemoglobin \< 75% of the lower limit of the normal range.
12. Systolic blood pressure \< 100 mmHg.
13. Acute or chronic physical impairment (other than dyspnea), limiting the ability to comply with study requirements.
14. Pregnant or breast-feeding.
15. Known concomitant life-threatening disease with a life expectancy \< 12 months.
16. Body weight \< 40 kg.
17. Any condition that prevents compliance with the protocol or adherence to therapy.
18. Recently started (\< 8 weeks prior to randomization) or planned cardio-pulmonary rehabilitation program based on exercise.
19. Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to randomization.
20. Systemic treatment within 4 week prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin (mTOR) inhibitors).
21. Treatment with cytochrome P3A (CYP3A) inducers within 4 weeks prior to randomization
22. Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients.
23. Planned treatment, or treatment, with another investigational drug within 1 month prior to randomization.

Answer: D