Dose-Confirming Study of Pulsed Inhaled Nitric Oxide in Subjects With WHO Group 3 Pulmonary Hypertension Associated With COPD

This is a placebo-controlled, double-blind, parallel, randomized dose-confirming clinical study characterizing the pharmacodynamic effects of pulsed iNO using the combination product, inhaled nitric oxide/INOpulse DS-C vs. placebo in subjects with PH associated with COPD on LTOT.

This study is designed to confirm the dose of inhaled nitric oxide (NO), administered through a pulsed delivery device (INOpulse® DS-C) that results in decreased pulmonary arterial systolic pressure (PASP) without significantly affecting systemic oxygenation. Subjects with COPD on long term oxygen therapy for at least 6 months will be screened to determine their PASP value; subjects with an elevated PASP will be eligible to be enrolled.

Subjects will undergo screening evaluations before randomization into a blinded 1:1:1:1 ratio (20 subjects/cohort) to receive 0.003, 0.010 or 0.015 mg/kg/IBW/hr of inhaled NO or placebo (nitrogen gas) for 20 minutes. The effect of the administered NO on change in PASP and oxygenation (PaO2) from Baseline will be determined.

• Pulmonary Hypertension
• Chronic Obstructive Pulmonary Disease

• Drug: Inhaled nitric oxide
• Other: Placebo
  Nitrogen gas

• Active Comparator: Inhaled NO 0.003 mg/kg IBW/hr
  Inhaled nitric oxide using a 3.0 mg/L [2440 ppm] NO minicylinder
  Intervention: Drug: Inhaled nitric oxide
• Active Comparator: Inhaled NO 0.010 mg/kg IBW/hr
  Inhaled nitric oxide using a 3.0 mg/L [2440 ppm] NO minicylinder
  Intervention: Drug: Inhaled nitric oxide
• Active Comparator: Inhaled NO 0.015 mg/kg IBW/hr
  Inhaled nitric oxide using a 6.0 mg/L [4880 ppm] NO minicylinder
  Intervention: Drug: Inhaled nitric oxide
• Placebo Comparator: Placebo
  Placebo (nitrogen gas) administered at a randomly assigned device setting of 0.003, 0.010 or 0.015 mg/kg IBW/hr (99.999% N2 minicylinder)
  Intervention: Other: Placebo

Inclusion Criteria:

1. Former smokers with at least 10 pack-years of tobacco cigarette smoking history before study entry and who have stopped smoking ≥ 1 month prior to enrollment
2. Age ≥ 40 years, ≤ 80 years
3. A confirmed diagnosis of COPD by the Global initiative for chronic Obstructive Lung Disease (GOLD) criteria
4. A post-bronchodilatory forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 0.7 and a FEV1 < 60% predicted (values obtained within 6 months of screening can be used unless obtained within ± 7 days of an exacerbation; otherwise, the test must be performed during screening)
5. Receiving LTOT for ≥ 3 months and ≥ 10 hours per day as determined by history
6. Echocardiogram with technical adequacy demonstrating TRV ≥ 2.9 m/s at Screening, as determined by a blinded central echocardiography laboratory
7. Females of childbearing potential must have a negative pre-treatment urine pregnancy test at Baseline (Day 1)
8. Signed informed consent prior to the initiation of any study mandated procedures or assessments

Exclusion Criteria:

1. Positive urine cotinine test
2. Currently using, or having used within the past month, a nicotine patch
3. A diagnosis of asthma or other non-COPD respiratory disease, in the opinion of the Investigator
4. Lack of patency of nares upon physical examination
5. Experienced an exacerbation requiring start of or increase in systemic oral corticosteroid therapy and/or hospitalization during the last month (ATS COPD Guidelines 2004)

6. 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 mm Hg as measured during cardiac catheterization within the past 6 months unless documented to have resolved by a subsequent cardiac catheterization
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)
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