Effect iNO on Functional Respiratory Imaging in Subjects With WHO Group 3 Pulmonary Hypertension With COPD on Oxygen
Effect iNO on Functional Respiratory Imaging in Subjects With WHO Group 3 Pulmonary Hypertension With COPD on Oxygen
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