Inhaled Nitric Oxide/INOpulse DS for Pulmonary Arterial Hypertension (PAH)

Study to determine if inhaled nitric oxide (iNO) given through a special delivery device
(INOpulse® DS) is safe and efficacious in treating Pulmonary Arterial Hypertension (PAH).
Medical literature and clinical experience suggests that iNO at pulsed doses of 0.013 to 0.1
mg/kg per hour for 1 month to 2+ years appears safe and suggests efficacy for the treatment
of pulmonary hypertension.

There are two parts to this study. In Part 1 (week 0 to week 16), the objectives are to
determine the safety, tolerability, efficacy, and exploratory objectives of two different
doses of iNO delivered by a pulsed delivery device in symptomatic subjects with PAH who
remain symptomatic due to PAH on approved PAH monotherapy or combination approved PAH
therapy. In Part 2 (week 17 to end of study Part 2 [EOS Part 2]), the objective is to compile
data on the long-term effects of iNO on safety, tolerability, clinical and hemodynamic
measures.

Inclusion Criteria:

1. Signed informed consent form (ICF) (and assent as appropriate) prior to the initiation
of any study mandated procedures or assessments

2. A confirmed diagnosis of Pulmonary Hypertension Group 1 (PAH) who have either
idiopathic PAH (IPAH), heritable PAH, anorexigen-induced PAH, associated PAH (APAH)
with connective tissue disease (CTD), APAH with repaired simple congenital systemic to
pulmonary shunt (i.e., atrial septal defect [ASD], ventricular septal defect [VSD]
and/or patent ductus arteriosus [PDA]; complete repair at least 1 year prior to
Screening) or APAH with human immunodeficiency virus (HIV)

3. Confirmation of PAH diagnosis at the time of Baseline RHC according to the following
definition: mPAP ≥ 25 mmHg at rest, with a concomitant mean pulmonary capillary wedge
pressure (mPCWP), mean left atrial pressure (mLAP), or left ventricular end diastolic
pressure (LVEDP) ≤ 15 mmHg and a PVR ≥ 240 dynes.sec/cm-5

4. 6MWD at least 100 meters and no greater than 450 meters

5. The subject is receiving at least one approved PAH therapy and is clinically
symptomatic from PAH (e.g., onset or increased dyspnea on exertion, dizziness,
near-syncope, syncope, chest pain or peripheral edema)

6. Background PAH medication doses (including calcium channel blockade if being used to
treat PAH) must be stable for at least 12 weeks prior to Screening

7. If on background conventional therapy (e.g., digoxin, diuretics, supplemental oxygen,
anticoagulation), it must have been started at least 30 days prior to Screening and be
on a stable dose for at least 30 days except for anticoagulation dose

8. If previously treated with an endothelin receptor antagonist (ERA),
phosphodiesterase-5 (PDE-5) inhibitor, prostacyclin or a prostacyclin analog and is no
longer on said treatment at Screening (per inclusion criteria as above), subject must
have been off said treatment for > 90 days at Screening

9. If previously treated with a calcium channel blocker as treatment for PAH and is no
longer on the calcium channel blocker treatment at Screening (per inclusion criteria
as above), subject must have been off the calcium channel blocker treatment for > 90
days at Screening

10. Age between 16 and 80 years (inclusive)

11. Male height ≤ 200 cm (6'7") or Female height ≤ 210 cm (6'11")

12. Subjects are willing and considered in the judgment of the Investigator able to use
the INOpulse DS device continuously for up to 24 hours per day

13. Females of childbearing potential must have a negative pre-treatment serum pregnancy
test and must be on a reliable method of contraception (including double protection if
appropriate, e.g., for subjects concurrently treated with bosentan therapy)

Exclusion Criteria:

1. Subjects with known HIV infection within the past 2 years who have a history of or
show any clinical or laboratory evidence of any opportunistic pulmonary disease (e.g.,
tuberculosis, Pneumocystis carinii pneumonia, or other pneumonias) at the time of
Screening

2. PAH associated with portal hypertension, untreated thyroid disorders, glycogen storage
disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies,
myeloproliferative disorders or splenectomy

3. Any subject with unrepaired congenital heart disease or repaired congenital heart
disease other than the simple congenital to systemic shunts specified in the inclusion
criteria, i.e., PAH associated with non-corrected simple congenital
systemic-to-pulmonary shunts, corrected simple congenital systemic-to-pulmonary shunt
with residual shunt post repair, or complex systemic-to- pulmonary shunts, corrected
or non-corrected, or any other complex congenital heart disease, corrected or
non-corrected

4. PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg),
known pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis

5. Any subject with WHO PH Groups 2, 3, 4 or 5

6. Left ventricular systolic dysfunction, i.e., left ventricular ejection fraction (LVEF)
< 40% or left ventricular shortening fraction (LVSF) < 22%

7. Left ventricular diastolic dysfunction, i.e., PCWP > 15 mmHg at rest or with exercise,
acute volume loading or pharmacologic testing

8. History of clinically significant cardiomyopathy or valvular heart disease (i.e.,
moderate or greater aortic insufficiency; moderate or greater aortic stenosis; or
moderate or greater mitral valve disease)

9. Clinically significant cardiac ischemic disease requiring use of nitrates, or hospital
admission for acute coronary syndrome or intervention (percutaneous coronary
intervention, coronary artery stent, coronary artery bypass surgery) within the past
90 days

10. Down syndrome

11. Any subject who develops a PCWP > 20 mmHg during AVT with iNO

12. Systemic hypertension defined as systolic blood pressure (SBP) > 160 mmHg and/or
diastolic blood pressure (DBP) > 100 mmHg persistent at Screening after a period of
rest (treated or untreated)

13. Systemic hypotension defined as SBP < 90 mmHg persistent at Screening after a period
of rest

14. Moderate to severe obstructive lung disease defined as both a forced expiratory volume
in 1 second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 65% of predicted value
(bronchodilator administration prior to testing is optional; the test should be done
within 3 years for all subjects with the exception of APAH/CTD which needs to be done
within 6 months prior to Screening)

15. Moderate to severe restrictive lung disease: total lung capacity (TLC) < 60% of
predicted; if TLC 60% to 70% predicted, a high resolution CT scan showing diffuse
disease or more than mild patchy disease (done within 3 years for all subjects with
the exception of APAH/CTD which needs to be done within 6 months prior to Screening)

16. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C

17. Estimated creatinine clearance < 30 mL/min (Cockcroft-Gault formula)

18. Hemoglobin < 10 gm/dL at Screening or Baseline

19. Acute or chronic physical impairment (other than dyspnea due to PAH) that would limit
the ability to comply with study procedures or adherence to therapy, including
carrying and wearing the INOpulse device per study protocol

20. Pregnant or breast-feeding at Screening

21. Administered L-arginine within 30 days prior to Screening

22. Known concomitant life-threatening disease with a life expectancy less than 1 year

23. Recently started (< 12 weeks prior to randomization) or planned cardiopulmonary
rehabilitation program to start within the 16 week controlled study

24. Atrial septostomy within 3 months of randomization

25. Any subject with PAH who is treatment naïve or receiving any unapproved therapy as
their only PAH treatment (including calcium channel blockade if the calcium channel
blockade is the only treatment for the PAH)

26. Any subject who requires the use of a continuous positive airway pressure (CPAP),
bilevel positive airway pressure (BiPAP), or other positive pressure devices to treat
obstructive sleep apnea

27. Medical problem(s) likely to preclude completion of Part 1

28. Use of investigational drugs or devices within 30 days prior to enrollment into the
study (other than acute vasodilator testing with iNO or IV epoprostenol)

29. Any underlying medical or psychiatric condition that, in the opinion of the
Investigator, makes the subject an unsuitable candidate for the study

30. Any condition other than the subject's PAH that, in that opinion of the investigator,
affects their ability to perform the 6MWT

31. Refusal to follow the protocol, including the two RHCs in Part 1 and one RHC in Part 2

32. Unable to travel to the investigational site for all required study visits and for all
additional visits per the judgment of the Investigator or Sponsor