Clinical Study of Pulsed, Inhaled Nitric Oxide Versus Placebo in Symptomatic Subjects With PAH

Phase 3, placebo controlled, double-blind, randomized, clinical study to determine safety,
tolerability and efficacy of pulsed inhaled nitric oxide (iNO) versus placebo as add-on
therapy in subjects with pulmonary arterial hypertension (PAH) who remain symptomatic on
approved PAH monotherapy or combination approved PAH therapy and long term oxygen therapy
(LTOT). (Part 1 and Part 2)

Inclusion Criteria:

1. Signed Informed Consent Form (and assent as appropriate) prior to the initiation of
any study mandated procedures or assessments

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

3. Subjects receiving at least one PAH specific therapy (ERA or PDE-5 inhibitor, or
inhaled, subcutaneous, or intravenous prostacyclin or a prostacyclin analog) with the
same type of therapy for at least 3 months with stable dosing 4 weeks prior to
Screening. (Subjects should be receiving optimal therapy according to the disease
severity)

4. Subjects using oxygen therapy by nasal cannula for at least 4 weeks prior to Screening

5. PAH diagnosis confirmed by RHC within the previous 5 years, according to the following
definitions:

- PVR ≥ 400 dynes.sec.cm-5 (5 Wood units)

- mPAP ≥ 25 mmHg

- PCWP or LVEDP ≤ 15 mmHg

- Subjects who otherwise meet all the inclusion criteria and none of the exclusion
criteria but have not undergone a RHC within the previous 5 years may be
considered eligible for the study if they undergo a RHC and then meet the
pulmonary hemodynamics criterion

6. 6MWD ≥ 100 meters and ≤ 450 meters prior to randomization

7. WHO Functional Class II-IV. Subjects with WHO Functional Class IV should be treated
with prostacyclin or a prostacyclin analog (subcutaneous or intravenous), plus at
least one additional PAH specific therapy (ERA or PDE-5), if available to the subject
and reimbursed by health insurance

8. Age between 18 and 85 years (inclusive)

9. Willingness to use INOpulse delivery device for at least 12 hours per day

10. Willingness to continue on study drug until the subject has completed Week 18
assessments

11. Female subjects of childbearing potential must have a negative pre-treatment pregnancy
test (serum or urine). All female subjects should take adequate precaution to avoid
pregnancy.

Exclusion Criteria:

1. Subjects with known HIV infection who have a history within the past 3 months of any
opportunistic pulmonary disease (e.g., tuberculosis, Pneumocystis carinii pneumonia, or
other pneumonias) at the time of Screening 2. PAH associated with untreated thyroid
disorders, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic
telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy 3. Subjects
with pulmonary conditions that may contribute to PAH including, but not limited to, chronic
bronchiectasis, cystic fibrosis, or other pulmonary condition that the Investigator may
deem to contribute to the severity of the disease or impair the delivery of iNO due to
airway disease 4. Subjects receiving riociguat 5. Subjects receiving oral prostanoids as
monotherapy 7. PAH associated with significant venous or capillary involvement, known or
suspected pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis 8. Any
subject with WHO PH Groups 2, 3, 4 or 5 9. Subjects with any of the following cardiac
abnormalities:

a. Underlying cardiomyopathy or clinically significant aortic or mitral valve disease in
the opinion of the investigator b. Left ventricular systolic dysfunction (LVSD), i.e., left
ventricular ejection fraction (LVEF) < 40% or left ventricular shortening fraction (LVSF) <
22%, as determined by local reading c. Current symptomatic coronary artery disease,
myocardial infarction within 1 year, or any coronary artery interventions within 6 months
10. 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) 11. Subjects with a history of deep vein thrombosis, pulmonary
embolism/infarction or prothrombotic disorder must have had chronic thromboembolic
pulmonary hypertension (CTEPH) excluded by ventilation/perfusion lung (V/Q) scan 12. Severe
obstructive lung disease defined as both a forced expiratory volume in 1 second/forced
vital capacity (FEV1/FVC) < 70% and FEV1 < 55% of predicted value 13. 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 14. Any subject who develops or has developed a PCWP > 20 mmHg during acute
vasodilator testing (AVT) 15. Systemic hypotension defined as SBP < 90 mmHg persistent at
Screening after a period of rest 16. Moderate to severe hepatic impairment, i.e.,
Child-Pugh Class B or C 17. On dialysis 18. 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 (i.e., 6MWT), including carrying and wearing the pulsed delivery
device per study protocol, or medical problem(s) likely to preclude completion of the study
19. Pregnant or breastfeeding females at Screening 20. Administered L-arginine within 1
month prior to Screening 21. Known concomitant life-threatening disease with a life
expectancy less than 1 year 22. Atrial septostomy within 3 months preceding randomization
23. The concurrent use of the INOpulse device with a continuous positive airway pressure
(CPAP), Bilevel positive airway presure BiPAP, or any other positive pressure device.

24. Use of investigational drugs or devices within 1 month prior to Screening (other than
acute vasodilator testing with iNO) 25. Any underlying medical or psychiatric condition
that, in the opinion of the Investigator, makes the subject an unsuitable candidate for the
study 26. Any subject who has been enrolled in any previous clinical study with inhaled NO
administered through pulse delivery.