Please select the eligibility criteria that correspond to the clinical trial below.
Title: PHIRST-1: Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of the Phosphodiesterase Type 5 (PDE5) Inhibitor Tadalafil in the Treatment in Patients With Pulmonary Arterial Hypertension
Brief Summary: The purpose of this study is to evaluate the safety and effectiveness of tadalafil for the treatment of pulmonary arterial hypertension.


Options:
A: Inclusion Criteria:

1. Subject must have completed Week 12 of AMB-320 (NCT00423748) or AMB-321 (NCT00423202) or must have received placebo during AMB-320 (NCT00423748) or AMB-321 (NCT00423202) and met two or more early escape criteria;
2. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form and must sign the form prior to the initiation of any study procedures.
3. Female subject of childbearing potential must agree to use two reliable methods of contraception until study completion and for at least four weeks following their final study visit. Reliable methods include: birth control pills/implants/injections, intrauterine devices (IUDs), spermicide, diaphragms, or condoms.

Exclusion Criteria:

* Subjects must have met the exclusion criteria of the AMB-320 (NCT00423748) and AMB-321 (NCT00423202)studies. In addition, a subject who meets any one of the following criteria is ineligible for participation in the study:

  1. Subject receiving bosentan, sildenafil, or iv inotropes at any time within four weeks prior to the AMB-320/321-E Screening/Randomization Visit;
  2. Subject receiving chronic prostanoid therapy (epoprostenol, treprostinil, iloprost, beraprost, or any other investigational prostacyclin derivative) within four weeks prior to the AMB-320/321-E Screening/RandomizationVisit;
  3. Female subject who is pregnant or breastfeeding;
  4. Subject with cardiovascular, liver, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject and/or efficacy of the study drug or severely limit the lifespan of the subject;
  5. Subject who has demonstrated noncompliance with previous medical regimens;
  6. Subject who has a recent history of abusing alcohol or illicit drugs;
  7. Subject who has participated in a clinical study involving another investigational drug or device at any time within four weeks prior to the AMB-320/321-E Screening/Randomization Visit.
B: 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.
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:

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: B