3 Part Study to Assess Inhaled Nitric Oxide on Functional Pulmonary Imaging in Subj. Pulmonary Hypertension Associated w/ COPD and IPF
3 Part Study to Assess Inhaled Nitric Oxide on Functional Pulmonary Imaging in Subj. Pulmonary Hypertension Associated w/ COPD and IPF
The objective of this exploratory study is to examine the utility of high resolution computed
 tomography (HRCT) to measure changes in functional pulmonary imaging parameters as a function
 of short term a) iNO administration and b) nitric oxide (NO) cylinder concentration using the
 investigational medical device INOpulse® DS-C in subjects with WHO Group 3 PH associated with
 COPD on LTOT (Part 1) and in Subjects with WHO Group 3 PH associated with Idiopathic
 Pulmonary Fibrosis (IPF) on LTOT (Part 2 and Part 3)
This is an exploratory, two-part, clinical study to evaluate the utility of HRCT to measure
 the pharmacodynamic effects of short term, pulsed administration of iNO using the combination
 product, inhaled nitric oxide/INOpulse in subjects with PH associated with COPD on LTOT. The
 utility of HRCT to characterize the effect of iNO on pulmonary imaging parameters as a
 function of a) short term inhaled iNO administration and b) NO cylinder concentration will be
 studied. In this study, pulmonary hypertension (PH) is defined as a tricuspid regurgitation
 velocity (TRV) ≥ 2.9 meters/second (m/s) or sPAP ≥ 38 mmHg by 2-D echocardiogram with Doppler
 or a mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg by right heart catheterization.

 Eleven subjects will be enrolled; the first 6 subjects enrolled will be assigned to Part 1,
 the next 2 subjects enrolled will be assigned to Part 2. After Part 1 has been completed and
 the results reviewed by the Sponsor, the next 4 subjects will be enrolled in Part 2. The Next
 three subjects will be participating in Part 3.

 In Part 1, six (6) subjects with adequate kidney function will be randomized to receive the
 30 mcg/kg IBW/hr doses of iNO using a cylinder concentration of 4880 ppm (6.0 mg/L).

 The 2 subjects enrolled in Part 2a will be randomly assigned to 1 of 2 sequences (2
 subjects/sequence) to receive iNO utilizing NO cylinder concentration (4880 ppm) at a dose of
 75 mcg/kg IBW/hr or Placebo set at a dose of 75 mcg/kg IBW/hr . The 2 patients from Part 2a
 will enter Part 2b. During Part 2b patients will receive iNO utilizing NO cylinder
 concentration (4880 ppm) at a dose of 75 mcg/kg IBW/hr (INOpulse® setting of 75 mcg/kg
 IBW/hr) for 4 weeks for at least 12 hours/day.

 The 3 subjects enrolled in Part 3a and 3b. Part 3a is dose titration visit, Part 3 is 4 weeks
 of treatment at dose identified in Paret 3a at the discretion of the Investigator. Part 3a:
 subjects will receive three different doses of iNO utilizing NO cylinder concentration of
 (4880ppm) at a dose of 5, 10 and 15 mcg/kg IBW/hr.

 The 3 patients from Part 3a will enter Part 3b and will be administered open label iNO for 4
 weeks/at least 12 hrs/day at the dose determined by the Investigator in Part 3a.

 Subjects will be replaced if they are unable to complete all treatment visits or of evaluable
 HRCT data cannot be obtained.
Inclusion Criteria:

 -  Subjects must meet all of the following inclusion criteria to be enrolled and eligible
 to participate in the study:

 1. A confirmed diagnosis of COPD by the Global initiative for chronic Obstructive
 Lung Disease (GOLD) criteria

 2. Pulmonary hypertension determined by one of the following within the past 12
 months:

 1. A right heart catheterization (not obtained within ± 7 days of an
 exacerbation) with an mPAP ≥ 25 mmHg, or

 2. An echocardiogram (not obtained within ± 7 days of an exacerbation) with a
 TRV ≥ 2.9 m/s or sPAP ≥ 38 mmHg (Note: a subject with an acceptable mPAP ≥
 25 mmHg determined by right heart catheterization will meet this inclusion
 criteria even with a TRV < 2.9 m/s)

 3. Current or former smokers with at least 10 pack-years of tobacco cigarette
 smoking before study entry

 4. Age ≥ 40 years, ≤ 80 years

 5. A post-bronchodilatory FEV1/FVC < 0.7 and a FEV1 < 60% predicted (values obtained
 within 6 months prior to screening can be used unless obtained within ± 7 days of
 an exacerbation; otherwise, the test must be performed during screening)

 6. Receiving LTOT for ≥ 3 months and ≥ 10 hours per day as determined by history

 7. Females of childbearing potential must have a negative pre-treatment urine
 pregnancy test

 8. Signed informed consent prior to the initiation of any study mandated procedures
 or assessments

 Exclusion Criteria:

 -  Subjects who meet any of the following criteria are not eligible for enrollment:

 1. A diagnosis of asthma or other non-COPD respiratory disease, in the opinion of
 the Investigator

 2. Lack of patency of nares upon physical examination

 3. Experienced during the last month an exacerbation requiring:

 1. start of or increase in systemic oral corticosteroid therapy and/or

 2. hospitalization

 4. Left ventricular dysfunction as measured by:

 1. Screening echocardiographic evidence of left ventricular systolic
 dysfunction (left ventricular ejection fraction [LVEF] < 40%), or

 2. Screening echocardiographic evidence of left ventricular diastolic
 dysfunction

 > moderate (i.e., > Grade 2), or

 3. Any history of pulmonary capillary wedge pressure (PCWP), left atrial
 pressure (LAP) or left ventricular end diastolic pressure (LVEDP) > 18 mmHg
 as measured during cardiac catheterization within the past 6 months unless
 documented to have resolved by a subsequent cardiac catheterization

 5. Renal impairment (i.e., an estimated GFRMDRD < 60 ml/min/1.73 m2) or history of
 renal failure using the equation (Levey et al., 2007):

 estimated GFRMDRD = 175×Scr -1.154×Age-0.203 ×1.212 (if black) ×0.742 (if female)

 where Scr = Standardized serum creatinine

 6. Known allergy to contrast media.

 7. Clinically significant valvular heart disease that may contribute to PH,
 including mild or greater aortic valvular disease (aortic stenosis or
 regurgitation) and/or moderate or greater mitral valve disease (mitral stenosis
 or regurgitation), or status post mitral valve replacement

 8. Use within 30 days of screening or current use of approved PH medications such as
 sildenafil or bosentan (use of Cialis® or Viagra® for erectile dysfunction is
 permitted)

 9. Use of investigational drugs or devices within 30 days prior to enrollment into
 the study

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