This was an exploratory open-label study and has met its initial objectives

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 long term iNO administrationusing the device INOpulse for 4 weeks in relation to Patient Reported Outcome (PRO) and exercise tolerance in subjects with WHO Group 3 PH associated with COPD on LTOT.

Changes from baseline to 4 weeks of pulsed iNO and after 2 weeks of withdrawal from pulsed iNO will be evaluated.

In this study, pulmonary hypertension (PH) is defined as systolic pulmonary arterial pressure (sPAP) ≥ 38 mmHg by 2-D echocardiogram with Doppler.

NO cylinder concentrations (4880 ppm) at a dose of 30 mcg/kg Ideal Body Weight (IBW)/hr (INOpulse setting of 30 mcg/kg IBW/hr) will be administered.

During the screening visit all the inclusion and exclusion criteria will be checked. Eligible patients will return to the site for visit 1. During visit 1 baseline HRCT scans with contrast agent will be obtained at Functional Residual Capacity (FRC) and Total Lung Capacity (TLC). Before the scans are taken a urine pregnancy test will be obtained in female patients with childbearing potential. A retest of the eGFR CKD-EPI value should also be performed before administering the contrast agent, if there is a clinical indication according to the investigator. The treatment will be started after all baseline assessments (physical examination, patency of nares, eGFR CKD-EPI determination, urine pregnancy test, HRCT scans, vital signs including oxygen saturation measurement, Electrocardiogram (ECG), Arterial Blood Gas (ABG), MetHb, 6-minutes walking distance (6MWD) (before and after the 6 MWD a Borg Category Ratio (Borg CR10) leg fatigue and dyspnea scale will be executed and during the 6MWD the oxygen saturation will be measured), PRO, spirometry). A second TLC and FRC scan with contrast agent during the iNO treatment will be taken. The scans will be taken whilst the patient is under iNO treatment for at least 20 minutes on the iNOpulse specific cannula. After the scans taken during the iNO treatment are performed some of the baseline assessments will be repeated whilst the patient is on iNO treatment (vital signs including oxygen saturation measurement, ABG, MetHb, 6MWD (before and after the 6 MWD a Borg CR10 leg fatigue and dyspnea scale will be executed and during the 6MWD the oxygen saturation will be measured), PRO, spirometry). During visit 1 the investigator will discontinue iNO to assess if rebound pulmonary hypertension occurs. In the first 2 patients, iNO therapy will be discontinued while 2D echo is performed to assess sPAP. Furthermore, NIBP, HR, SpO2 will be measured. In the remaining patients the following additional safety assessments (NIBP, HR, SpO2) will be performed while the patient is discontinued at least 20 minutes of iNO. If the investigator considers it is safe to restart the iNO-therapy, the patient will start chronic iNO treatment. After the results of the safety assessments of the 2 first patients are collected a safety meeting will be held to evaluate the results. Depending on the results, the additional 2D echo may be performed in additional patients. Subjects will be contacted via telephone or e-mail ± 24 hours after visit 1, for assessment of vital status, concomitant medications and the occurrence of new AEs or worsening of previously existing recorded AEs and PRO (= visit 2). After 2 weeks of treatment of iNO with a dosage of 30 mcg/kg IBW/hr during at least 12 hours a day patients will be asked to return to the site for visit 3. During that visit following measurements will be performed: patency of nares will be checked, vital signs including oxygen saturation measurement, MetHb, 6MWD (with Borg CR10 leg fatigue and dyspnea scale and oxygen saturation measurement), PRO and AE assessment. After 4 weeks treatment visit 4 will be conducted. 2D - echocardiogram with Doppler (immediately after the 2D - echocardiogram with Doppler NIBP, HR, SpO2 will be measured) and HRCT scans with contrast agent under iNO pulse will be taken. Before the scans are taken an urine pregnancy test will be obtained, if applicable. A retest of the eGFR CKD-EPI value should also be performed before administering the contrast agent, if there is a clinical indication according to the investigator. Spirometry assessments will be performed, patency of nares, ECG, ABG, MetHb, 6MWD (with Borg CR10 fatigue and dyspnea scale and oxygen saturation measurement), PRO will be assessed. After all assessments are completed, iNO will be discontinued. Twenty minutes after discontinuation of iNO-therapy, spirometry, PRO, MetHb, 6MWD (before and after the 6 MWD a Borg CR10 leg fatigue and dyspnea scale will be executed and during the 6MWD the oxygen saturation will be measured) and 2D-echocardiogram with Doppler measurements measurement will be repeated. Vital signs with oxygen saturation will be measured immediately after the 2D-echocardiogram with Doppler. After all the assessments the patient is placed back on his/her prescribed dose of LTOT using their usual cannula. The patient will be assessed for any signs of acute withdrawal. Therefore vital signs including oxygen saturation will be measured.

At visit 5, two weeks after discontinuation of iNO treatment repeat vital signs with oxygen saturation measurement, physical examination, patency of nares, spirometry, 2D-echocardiogram with Doppler (immediately after the 2D - echocardiogram with Doppler NIBP, HR, SpO2 will be measured), ABG, MetHb, 6MWD(with Borg CR10 leg fatigue and dyspnea scale and oxygen saturation measurement), and PRO will be performed. If applicable a last urine pregnancy test will be executed to make sure no pregnancy occurred during the study. If there are no follow-up actions for a patient at this visit, it will be considered as a completion of study participation / end of study for that particular patient.

Inclusion Criteria:

- 1. Male or female patient 2. A confirmed diagnosis of COPD by the Global initiative for chronic Obstructive Lung Disease (GOLD) criteria 3. Pulmonary hypertension will be defined as sPAP ≥ 38 mmHg as determined by echocardiogram (not obtained within ± 7 days of an exacerbation) within the past 12 months.

4. Current or former smokers with at least 10 pack-years of tobacco cigarette smoking before study entry 5. Age ≥ 40 years, ≤ 85 years 6. 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) 7. Receiving LTOT for ≥ 3 months and ≥ 10 hours per day as determined by history 8. Females of childbearing potential must have a negative pre-scan urine pregnancy test 9. Signed informed consent prior to the initiation of any study mandated procedures or Assessments

Exclusion Criteria:

• 1. Males who have the intention to father a child during the study. 2. A diagnosis of asthma or other non-COPD respiratory disease, in the opinion of the Investigator 3. Lack of patency of nares upon physical examination 4. Experienced during the last month an exacerbation requiring:

  1. start of or increase in systemic oral corticosteroid therapy and/or
  2. hospitalization 5. 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 3), 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 6. Renal impairment (i.e., an estimated GFR CKD-EPI < 30 ml/min/1.73 m2) or history of renal failure using the equation:

     Men:

     crs< 0.9 mg/dL: eGFRCKD-EPI = 141 × (crs /0.9)-0.411 × 0.993Age crs≥ 0.9 mg/dL: eGFRCKD-EPI = 141 × (crs /0.9)-1.209 × 0.993Age

     Woman:

     crs< 0.7 mg/dL: eGFRCKD-EPI = 144 × (crs /0.7)-0.329 × 0.993Age crs≥ 0.7 mg/dL: eGFRCKD-EPI = 144 × (crs /0.7)-1.209 × 0.993Age where crs= Normal and elevated serum creatinine Subjects with possible compromised kidney function (i.e., Glomerular Filtration Rate estimated using the Modification of Diet in Renal Disease equation [eGFR CKD-EPI] between 30 and 60 ml/min/1.73 m2) may be enrolled provided the Radiology Department and Principal Investigator review the medical records of subjects with an eGFR CKD-EPI between 30 and 60 ml/min/1.73 m2 in order to confirm the contrast agent can be safely administered to these subjects and approval by both the Radiology Department and Principal Investigator must be obtained before enrolling these subjects.

     7. Known allergy to contrast media. 8. 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 9. 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) 10. Use of investigational drugs or devices within 30 days prior to enrollment into the study 11. Any underlying medical or psychiatric condition that, in the opinion of the Investigator, makes the subject an unsuitable candidate for the study