Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multi-centre, Multinational, Open-label, Single-dose Acute Hemodynamic Study Followed by Multi-centre, Multinational, Randomized, Double-blind, Parallel-group, Placebo Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy (Proof-of-concept) of ACT-293987 (NS-304) in the Treatment of Pulmonary Arterial Hypertension in Subjects Aged 18 Years and Over
Brief Summary: This is a multi-centre, multinational, open-label, single-dose acute hemodynamic study followed by randomized, double-blind, parallel-group, placebo controlled study. Eligible subjects will undergo an open-label, single-dose acute hemodynamic study with ACT-293987(NS-304) and 21 weeks of double-blind treatment during which subjects will receive either ACT-293987 (NS-304) or placebo b.i.d. Subjects who have completed the double-blind study can enter the open extension study (separate protocol) and receive administration of ACT-293987 (NS-304) if the subject wishes and the Investigator considers it appropriate.


Options:
A: Inclusion Criteria:

* Between 12 and 70 years of age, inclusive.
* Body weight at least 45 kg (approximately 100 pounds).
* PAH that is either idiopathic/heritable (including PAH associated with appetite suppressant/toxin use); PAH associated with repaired congenital systemic-to-pulmonary shunts (repaired ≥ 5 years); PAH associated with collagen vascular disease; or PAH associated with HIV.
* Baseline 6-minute walk distance between 150 and 450 meters, inclusive.
* Currently receiving an approved endothelin receptor antagonist and/or an approved phosphodiesterase-5 inhibitor for at least 90 days and on a stable dose for at least the last 30 days.
* Previous testing (e.g., right heart catheterization, echocardiography) consistent with the diagnosis of PAH.
* Reliable and cooperative with protocol requirements.

Exclusion Criteria:

* Nursing or pregnant.
* Received a prostacyclin within the past 30 days.
* PAH due to conditions other than noted in the above inclusion criteria.
* History of uncontrolled sleep apnea, renal insufficiency, anemia, left sided heart disease, uncontrolled systemic hypertension, or parenchymal lung disease.
* Use of an investigational drug within 30 days of Baseline.
B: Inclusion Criteria: Patients Must

1. Between 16- 75 years of age.
2. Male or, if female, physiologically incapable of childbearing or utilizing birth control.
3. Have current diagnosis of symptom-limited NYHA Functional Class III/IV PAH that is:

   * PPH ("idiopathic" or familial PAH); or
   * PAH associated with collagen vascular disease (confirmed by antinuclear antibody titer or acceptable test); or
   * PAH associated with HIV infection (confirmed by serological test).
4. If HIV positive, have CD4 lymphocyte count ≥ 200 at baseline and receiving current SOC anti-retroviral or effective medication for HIV infection.
5. Optimally treated with conventional PH therapy and clinically stable for at least 1 month prior to baseline.
6. Have ventilation/perfusion scan, contrast-enhanced CT scan, or pulmonary angiogram after onset of PAH that rules out pulmonary embolism.
7. Have cardiac catheterization in last 3 months (or at Baseline) showing:

   * PAPm \> 35 mmHg (at rest) \&
   * PCWPm (or LV end diastolic pressure) \< 16 mmHg \&
   * PVR \> 5 mmHg/L/min.
8. Have echocardiogram in last 3 months consistent with PH, specifically:

   * evidence of RV hypertrophy or dilation \&
   * evidence of normal LV function \&
   * absence of mitral valve stenosis.
9. Have chest radiograph consistent with PH performed in last 3 months. Radiograph must show clear lung fields or no more than patchy interstitial infiltrates.
10. Unless contraindicated, able to receive one of following anticoagulants: warfarin to achieve INR between 1.5-2.5 or heparin to produce aPTT between 1.3-1.5 times control, unless higher levels clinically indicated.
11. Mentally and physically capable of learning to administer Study Drug using ambulatory intravenous infusion pump and central venous access, or have trained caregiver.
12. If on corticosteroids, receiving stable dose of 20 mg/day of prednisone (or equivalent dose of another steroid) for at least 1 month prior to entry.

Exclusion Criteria: Patients must not:

1. Nursing or pregnant (women of childbearing potential have negative pregnancy test).
2. Have had new type of chronic therapy (including but not limited to oxygen, different category of vasodilator, diuretic, digoxin) for PH, except for anticoagulants, added in last month.
3. Be scheduled for heart-lung transplant.
4. Have any PH medication except for anticoagulants discontinued in week prior to study entry.
5. Have received any chronic prostaglandin or prostaglandin analogue (including intravenous/inhaled/oral: epoprostenol, iloprost, beraprost, etc.), any phosphodiesterase inhibitor therapy such as sildenafil, or any endothelin antagonist therapy such as bosentan, in past 30 days.
6. Have PH associated with chronic thromboembolic disease; or chronic obstructive lung diseases or hypoxemia; or evidence of significant parenchymal lung disease as evidenced by PFTs in last 3 months as follows (any one of following):

   * TLC \< 60% (predicted) or high resolution CT documenting diffuse interstitial fibrosis or alveolitis
   * FEV1/FVC ratio \< 50%
7. Have Portal Hypertension.
8. Have history of uncontrolled Sleep Apnea, defined as oxygen desaturation less than 90% at night, in past 3 months.
9. Have history of left-sided heart disease including:

   * Aortic or mitral valve disease or
   * Pericardial constriction or
   * Restrictive or congestive cardiomyopathy; or have evidence of current left-sided heart disease defined by:
   * PCWPm or LV end diastolic pressure \> 16 mmHg or
   * LVEF \< 40% by MUGA, angiography or echocardiography or
   * LV Shortening Fraction \< 22% by echocardiography or
   * Symptomatic coronary disease (demonstrable ischemia).
10. Have any disease other than HIV or connective tissue disease associated with PH (e.g. sickle cell anemia, schistosomiasis).
11. Have active AIDS or tuberculosis.
12. Have musculoskeletal disorder (e.g. arthritis, artificial leg, etc.) or any other disease thought to limit ambulation, or connected to machine which is not portable.
13. Have baseline exercise capacity of \<50 m or \>325 m as measured by 6-Minute Walk Test.
14. Have uncontrolled systemic hypertension as evidenced by systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg.
15. Have used prescription appetite suppressants in 3 months of study entry.
16. Have chronic renal insufficiency defined by creatinine \>2.5 mg/dL or requiring dialysis.
17. Receiving an investigational drug (other than acute challenge with epoprostenol), have in place an investigational device, or have participated in investigational drug/device study in past 30 days.
18. Have presence of any physiological or mental condition which contraindicates administration of Remodulin.
C: Inclusion Criteria:

1. Male and female subjects 18 years of age or older with symptomatic PAH despite treatment with anticoagulants, calcium channel blockers, diuretics, cardiac glycosides, supplemental oxygen, endothelin-receptor antagonists and/or phosphodiesterase inhibitors. Endothelin receptor antagonists and phosphodiesterase inhibitors must have been used at a stable dose for more than 12 weeks before screening.
2. Subjects with idiopathic PAH, familial pulmonary arterial hypertension and PAH associated with collagen vascular disease, corrected congenital vitium (congenital systemic to pulmonary shunts surgically repaired at least five years before) or anorexigen use.
3. Diagnosis of PAH established according to the standard criteria:

   1. Resting mean pulmonary arterial pressure \> 25 mmHg.
   2. PVR \> 240 dynes s/cm5.
   3. Pulmonary capillary wedge pressure or left ventricular end diastolic pressure \< 15 mmHg.
4. PVR \> 400 dynes s/cm5.
5. Two 6MWTs between 150 and 500 m (inclusive) with the variation in 6MWT within ± 15% between the two tests despite other treatments for PAH.

   - Two 6MWT values are needed. Only one 6MWT should be performed at screening for confirmation of eligibility if 6MWT has been previously conducted within six weeks of the screening visit unless the subject was taking another investigational drug or participating in a specific training and exercise programme at the time of the previous test.
6. Subjects who are able and willing to refrain from sunbathing, prolonged sun exposure, and solarium use, and to limit skin and eye exposure to sunlight using appropriate precautions (protective clothing, sunscreen and sunglasses) from the first dose until 14 days after study drug discontinuation.

Exclusion Criteria:

Subjects will not be entered in the study for any of the following reasons:

1. Subjects with clinically unstable right heart failure within the last three months (NYHA Class IV).
2. Subjects who have received or have been scheduled to receive long-term treatment with epoprostenol within three months before screening.
3. Hypotensive subjects (systemic systolic blood pressure \< 85 mmHg).
4. Subjects with PAH associated with portal hypertension, Human Immunodeficiency Virus infection or unrepaired congenital systemic to pulmonary shunts.
5. Subjects with ventilation-perfusion lung scan or pulmonary angiography indicative of thromboembolic disease.
6. Subjects with significant obstructive (forced expiratory volume in one second \[FEV1\]/forced vital capacity \[FVC\] \< 70% predicted) or restrictive (total lung capacity \< 70% predicted) lung disease.
7. In collagen vascular diseases, subjects with significant interstitial disease (FVC \< 70% predicted).
8. Subjects with evidence of left sided heart disease.
9. Subjects with moderate or severe hepatic impairment (Child-Pugh B and C).
10. Subjects with clinically significant chronic renal insufficiency (estimated creatinine clearance \< 30 mL/minute, or serum creatinine \> 2.5 mg/dL).
11. Subjects who are receiving or have been receiving any investigational drugs within 30 days before screening.
12. Subjects with musculoskeletal disorder limiting ambulation.
13. Females who are breast-feeding, pregnant or plan to become pregnant during the study and females who are not using a highly effective method of birth control (failure rate less than 1% per year) such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomised partner.
D: Inclusion Criteria:

* A subject is eligible for inclusion in this study if all of the following criteria apply:
* Between 18 and 75 years of age, inclusive.
* Body weight at least 40 kg (approximately 90 lbs.)
* PAH that is either idiopathic/heritable; associated with appetite suppressant or toxin use; associated with collagen vascular disease; associated with repaired congenital shunts; associated with HIV.
* Currently receiving an approved endothelin receptor antagonist and/or an approved phosphodiesterase-5 inhibitor for at least 90 days and on a stable dose for at least the last 30 days.
* Baseline six-minute walk distance (6MWD) between 150-425 meters
* Previous testing (e.g., right heart catheterization, echocardiography) consistent with the diagnosis of PAH.
* Reliable and cooperative with protocol requirements.

Answer: C