Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase 3 Study to Evaluate the Effects of Macitentan on Exercise Capacity in Subjects With Eisenmenger Syndrome
Brief Summary: Clinical study to assess the efficacy, safety, and tolerability of macitentan in subjects with Eisenmenger Syndrome.


Options:
A: 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.
B: Inclusion Criteria:

* Subjects:

  * not participating in the hemodynamic sub-study: males or females ≥ 12 years of age.
  * participating in the hemodynamic sub-study: males or females ≥ 18 years of age.
* Subjects (including those with Down Syndrome \[DS\]) with confirmed Eisenmenger Syndrome \[ES\] (European Society of Cardiology \[ESC\] and the European Respiratory Society \[ERS\] guidelines):

  1. Established by echocardiography as:

     * Large congenital shunting defect at atrial, ventricular or arterial level\*
     * and right to left shunt or bi-directional shunt with prevalent right to left direction.
  2. Resting peripheral oxygen saturation (SpO2) ≤ 90% and \> 70% (pulse oximetry, room air).

The lower limit is 65% if a subject is living at an altitude greater than 2500 m above sea level.

\*Subjects with any of the following open defects are eligible for the study either as an isolated defect or in combination:

* atrial septal defect (ASD)
* ventricular septal defect (VSD)
* partial or complete atrioventricular septal defect (AVSD)
* patent ductus arteriosus (PDA)
* aortopulmonary window (AP window)
* total or partial anomalous pulmonary venous return (TAPVR, PAPVR) The defects may be either unoperated or previously palliated surgically (provided significant residual defect remains).

The Steering Committee will review the echocardiography data of all subjects (main study and sub study) to confirm eligibility prior to Randomization.

* Subjects with the following findings at cardiac catheterization:

  * Mean resting pulmonary arterial pressure (mPAP) \> 25 mmHg
  * Pulmonary capillary wedge pressure (PCWP) or mean left atrial pressure (LAP) or left ventricular end diastolic pressure (LVED) ≤ 15 mmHg
  * Pulmonary vascular resistance (PVR) ≥ 800 dyn∙s/cm5 or ≥ 10 Wood units
* Subjects with WHO functional class ≥ II.
* Subjects able to reliably perform the the 6-minute walk test (6MWT) with a minimum distance of 50 m and a maximum distance of 450 m.

Exclusion Criteria:

- Main study and hemodynamic sub-study: Any of the following conditions previously known or identified via cardiac catheterization or echocardiography:

* Pulmonary arterial or venous stenosis \> 25% size of native pulmonary artery (PA) or pulmonary vein
* Severe tricuspid regurgitation in the setting of left to right shunt at the ventricular or atrial level
* Greater than mild tricuspid stenosis
* Intracavitary RV outflow obstruction
* Greater than mild mitral stenosis
* Intracavitary LV outflow obstruction
* Subvalvular or supravalvular aortic stenosis
* Aortic coarctation
* Greater than moderate mitral regurgitation
* Recognized extracardiac systemic venous collaterals to the pulmonary venous circulation
* Recognized hepatic wedge pressure-inferior vena cava pressure gradient \>12 mm Hg
* PCWP "v" waves \>20 mmHg
* Tetralogy of Fallot
* Truncus arteriosus
* Interrupted aortic arch
* Transposition of great arteries
* Single ventricle defects: absent AV connection (mitral or tricuspid atresia), double inlet AV connections left or right ventricle, functional univentricular heart (unbalanced AVSD, hypoplastic RV, double outlet RV), hypoplastic left heart syndrome
* Ebstein's anomaly
* Severe aortic regurgitation
* Pulmonary atresia
* PAPVR or TAPVR, ONLY if there is lung hypoplasia or if documentation confirming the absence of lung hypoplasia does not exist.

For subjects participating in the hemodynamic sub-study the following will also be considered exclusion criteria:

* SVC stenosis \>25% size of native vessel
* PDA, AP window, TAPVR, PAPVR, or ASD sinus venosus with anomalous pulmonary veins
* Down Syndrome

  * Subjects with deterioration of their clinical status within 3 months prior to Screening or during the Screening period.
  * Known moderate-to-severe restrictive (i.e., total lung capacity \[TLC\] \< 60% of predicted value) or obstructive lung disease (i.e., forced expiratory volume in one second \[FEV1\] \< 80 % of predicted value, and with FEV1 / forced vital capacity \[FVC\] \< 70%)
  * Treatment with prostanoids within 1 month prior to Randomization
  * Subjects who initiated a PDE-5 inhibitor within 1 month prior to Randomization or those on a PDE-5 inhibitor for whom the dose has not been stable within 1 month prior to Randomization
  * Treatment with endothelin receptor antagonists (ERAs) within 1 month prior to Randomization
  * Subjects who initiated diuretics within 1 week prior to Randomization or subjects whose diuretic treatment has not been stable for at least 1 week prior to Randomization
  * Subjects being considered for an organ transplant
C: Inclusion Criteria:

* Normal healthy subjects aged 18 - 55 years

Exclusion Criteria:

* Pregnancy
* Heart, lung or liver disease
* Use of glyburide, cyclosporin A
D: Inclusion Criteria:

* Signed informed consent prior to any study-mandated procedure
* No contra-indication to stop (according to label) anti-hypertensive treatment(s) at screening
* Mild-to-moderate essential hypertension with or without ongoing anti-hypertensive treatment(s):

  -- Mean (of 5 measurements) sitting diastolic blood pressure (SiDBP) ≥ 90 to \< 110 mmHg measured by office blood pressure measurements (OBPM).
* Women of childbearing potential must have a negative pregnancy test and use of reliable methods of contraception

Exclusion Criteria:

* Severe hypertension (grade 3): mean sitting systolic/diastolic BP (SiSBP/SiDBP; measured by OBPM) ≥ 180/110 mmHg, respectively.
* Secondary hypertension
* Known hypertensive retinopathy greater than Keith-Wagener Grade 2
* Myocardial infarction, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft within 12 months prior to randomization
* Unstable angina within 6 months prior to randomization
* Heart failure New York Heart Association class III and IV
* Valvular defects (such as severe aortic or mitral valve disease) and/or hemodynamically relevant rhythm disturbances
* Clinical evidence of cerebrovascular insufficiency or a cerebrovascular accident within 6 months prior to randomization.
* Subjects working night shifts
* Body mass index \< 20 kg/m2 or \> 40 kg/m2
* Treatment with any medication which may affect BP (e.g., treatment of psychiatric diseases, ophthalmic preparations)
* Treatment with strong cytochrome P450 3A4 (CYP3A4) isoenzyme inhibitors or inducers
* Treatment with guanethidine and/or mineralocorticoid receptor antagonists within 1 month prior to Screening (Visit 1)
* Treatment with another investigational treatment within 1 month prior to Screening (Visit 1)
* Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol

Answer: B