IKARIA

A PHASE 2, 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 SYMPTOMATIC SUBJECTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH)

Inclusion Criteria:

(1) A confirmed diagnosis of Pulmonary Hypertension Group 1 (PAH)

(2) 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

(3) 6MWD at least 100 meters and no greater than 450 meters

(4) 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)

(5) Age between 16 and 80 years (inclusive)

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

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

(3) 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)

(4) Systemic hypotension defined as SBP < 90 mmHg persistent at Screening after a period of rest

(5) 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)

(6) 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)

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

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