Please select the eligibility criteria that correspond to the clinical trial below.
Title: Early Treatment of Borderline Pulmonary Arterial Hypertension Associated With Systemic Sclerosis (SSc-APAH) A Randomized, Controlled, Double-blind, Parallel Group, Proof-of-concept Trial EDITA
Brief Summary: Trial Design Patients with borderline PAH indicated by borderline mPAP values will be included in this single centre study. This clinical investigation is performed as a Proof-of-Concept (PoC) investigator initiated trial (IIT) using a prospective, randomized, double-blind, parallel group, placebo-controlled, phase IIA clinical study design. On their first visit their medical history will be obtained and physical examination will be conducted. Moreover, an electrocardiogram (ECG), laboratory testing (NT-proBNP, uric acid and other laboratory tests), echocardiography at rest and right heart catheterization will be carried out. If patients have been identified within the last 6 months before screening investigations by right heart catheterization, the measurements are considered valid as baseline investigations and will not be repeated. If patients fulfill the inclusion criteria and still suffer from borderline mPAP values they will be invited to join the study. The clinical investigations will begin within 28 days. The prospective study will comprise a 6 months study period (180 ±2 weeks) plus the screening phase up to 28 days and a follow-up phase of 30 ±7 days.


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:

* Male or females from 40 to 80 years of age
* Diagnosis of IPF
* Honeycombing (fibrosis in the lung) on high-resolution computerised tomography (HRCT) scan of less than or equal to 5%
* Willing and able to have 2 right heart catheterizations performed
* Willing to have monthly lab tests to monitor liver function
* Able to perform the 6 minute walk test (indicated adequate physical function)
* Must have meet lung function requirements
* Normal liver function tests
* Negative serum pregnancy test
* Willing to use at least 2 reliable methods of contraception
* Able to understand and willing to sign informed consent form

Exclusion Criteria:

* No restrictive lung disease (other than usual interstitial pneumonia or IPF)
* No obstructive lung disease
* No recent or active respiratory exacerbations
* No recent hospitalization for an IPF exacerbation
* No recent history of alcohol abuse
* Chronic sildenafil (or same drug class) use for pulmonary hypertension
* Chronic treatment with certain medications for IPF within 30 days of randomization
* No other serious medical conditions
C: Inclusion Criteria:

* Patients with known sarcoidosis 21.
* Age 18 or greater
* Patients with documented pulmonary hypertension with a PA mean \> 25 mm Hg as measured by cardiac catheterization within six months of entry into the study. Pulmonary artery occluding pressure and or left ventricular end diastolic pressure must be less than 15 mm Hg.
* Patients with WHO class II or III
* Six minute walk distance of between 100 to 500 meters
* Patients on stable immunotherapy for their sarcoidosis, including prednisone, methotrexate, azathioprine, hydroxychloroquine, cyclophosphamide, thalidomide, and/or infliximab
* Patients able to provide written consent

Exclusion Criteria:

* Patients on pulmonary vasodilator drugs (flolan, remodulin, bosentan, sildenafil) n the prior 28 days. Patients on stable dose of calcium channel blocker for more than 1 month prior to right heart catheterization can be continued on the calcium channel blocker.
* Patients with severe airway obstruction as defined by FEV1/FVC of less than 35%
* Patients with World Health Organization (WHO) class IV status.
* Patients who are pregnant or breast feeding
* Patients with significant left ventricular dysfunction with a left ventricular ejection fraction of less than 35%
* Cardiac index \< 2.0 liters and/or right atrial pressure \>15 mm Hg
* Significant liver dysfunction not due to sarcoidosis.
* Patients with severe other organ disease felt by investigators to impact on survival during the course of the study.
* Patients unable to perform the 6 minute walk study
D: Inclusion Criteria:

1. mPAP 21-24 mmHg, TPG \> 11mmHg, PAWP \<15 mmHg and/or
2. Exercise induced elevated mPAP-values \>30 mmHg, PAWP \<18 mmHg; TPG \>15 mmHg, as defined in Saggar et al. (2012) without left heart or severe lung disease or systemic arterial hypertension
3. Adult patients having completed his/her 18th birthday
4. Patients with definite diagnosis of Systemic Sclerosis using the scleroderma criteria of the American Rheumatism Association
5. SSc-disease duration \>3 years
6. Able to understand and willing to sign the Informed Consent Form
7. Negative pregnancy test at the start of the trial and appropriate contraception throughout the study for women with child-bearing potential.

Exclusion Criteria:

1. Any connective tissue diseases (CTD) other than SSc
2. Pulmonary hypertension (PH) confirmed by right heart catheter (RHC) before enrolment, i.e. mPAP ≥25 mmHg at rest
3. Patients presenting normal mPAP values, that is mPAP\<21 mmHg at rest, ≤30 mmHg during exercise, PAWP \>=15 mmHg at rest or \<=18 mmHg during exercise
4. Ongoing or a history of \>2 weeks of continued use of therapies that are considered definitive PH treatment: endothelin receptor antagonists (ERA; e.g. bosentan, ambrisentan), phosphodiesterase type 5 inhibitors (PDE5; e.g. sildenafil, tadalafil, vardenafil), prostanoids (e.g. epoprostenol, treprostinil, iloprost, beraprost) and soluble guanylate cyclase stimulator (e.g. Riociguat). Intermittent use of PDE5 inhibitors for male erectile dysfunction is permitted.
5. Except for diuretics and corticosteroids medical treatment should not be expected to change 4 weeks prior inclusion into the study and during the entire 12-week study period.
6. Known intolerance to ambrisentan or one of its excipients
7. Clinically significant anemia (hemoglobin concentration of less than 75% of the lower limit of normal, LLN)
8. Forced vital capacity (FVC) \<60%, forced expiratory volume in first second (FEV1) \<65%
9. Severe interstitial lung disease, idiopathic pulmonary fibrosis
10. Renal insufficiency (glomerular filtration rate \[GFR\] \<60 mL/min/1.73m2 for at least 3 months)
11. Baseline values of hepatic aminotransferases (ALT and/or AST) \>3 x upper limit of normal (ULN)
12. Systolic blood pressure \<85 mmHg;
13. evidence of inadequately treated blood pressure \>160/90 mmHg and/or blood pressure during exercise \>220/120 mmHg
14. Patients referred with clinically significant overt heart failure
15. Clinically significant fluid retention
16. Previous evidence or diagnosis of clinically relevant left heart disease, i.e. at least one of the following: Previous echocardiography with estimated left ventricular (LV) ejection fraction \<50%, previous history of cardiogenic pulmonary edema, increased size of left atrium (\>50 mm)
17. Known significant diastolic dysfunction associated with clinical heart failure
18. Known coronary disease or significant valvular heart disease
19. Known congenital heart defects such as single ventricle, transposition, Eisenmenger
20. Known hypertrophic cardiomyopathy or left ventricular hypertrophy (interventricular septum thickness (IVS) or posterior wall thickness (PWD) \>1.2 cm)
21. Participation in any clinical drug trial within 4 weeks prior to screening of this study and/or who is scheduled to receive another investigational medicinal product (IMP) during the course of this study
22. Pregnancy or lactation

Answer: D