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

Study Overview
=================
Brief Summary
-----------------
This is a placebo-controlled, double-blind, parallel, randomized, two-part, 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 World Health Organization (WHO) Group 3 pulmonary hypertension (PH) associated with Chronic Obstructive Pulmonary Disease (COPD) on Long Term Oxygen Therapy (LTOT).

Detailed Description
-----------------
This two-part study is designed to confirm the dose of inhaled nitric oxide (NO), administered through an investigational pulsed delivery device (INOpulse® DS-C) that results in decreased pulmonary arterial systolic pressure (PASP) without significantly affecting systemic oxygenation. In Part A, 80 subjects will be randomized to 1of 4 treatment groups in a 1:1:1:1 ratio (with 20 subjects in each treatment group). Subjects assigned to an iNO group will receive pulsed iNO at a dose of 0.003 mg/kg IBW/hr, 0.010 mg/kg IBW/hr, or 0.015 mg/kg IBW/hr, with a set pulse width (PW) of 260 milliseconds (ms). Part A subjects assigned to the placebo group will receive nitrogen (N2) at a randomly assigned device setting of 0.003, 0.010 or 0.015 mg/kg IBW/hr with a set PW of 260 ms. Subjects who were randomized in Part A are permitted to participate in Part B of the study. Subjects will need to be re-screened and re-randomized for Part B participation. In Part B, 60 subjects will be randomized to 1 of 3 treatment groups in a 1:1:1 ratio (with 20 subjects in each treatment group). Subjects assigned to an iNO group will receive pulsed iNO at either 0.030 mg/kg IBW/hr or 0.075 mg/kg IBW/hr, with a set PW of 260 ms. Part B subjects assigned to placebo will receive N2 at a randomly assigned device setting of 0.030 mg/kg IBW/hr or 0.075 mg/kg IBW/hr with a set PW of 260 ms. Part B will use a skewed block randomization scheme with 10 blocks of 6 subjects as follows: Blocks 1-3: 3 subjects at 0.030 mg/kg IBW/hr, 1 subject at 0.075 mg/kg IBW/hr, and 2 subjects randomly assigned to placebo either 0.030 or 0.075 mg/kg IBW/hr Blocks 4-7: 2 subjects at 0.030 mg/kg IBW/hr, 2 subjects at 0.075 mg/kg IBW/hr, and 2 subjects randomly assigned to placebo either 0.030 or 0.075 mg/kg IBW/hr Blocks 8-10: 1 subject at 0.030 mg/kg IBW/hr, 3 subjects at 0.075 mg/kg IBW/hr, and 2 subjects randomly assigned to placebo either 0.030 or 0.075 mg/kg IBW/hr

Official Title
-----------------
A Placebo-Controlled, Double-Blind, Parallel, Randomized, Two-Part, Clinical Dose-Confirming Study Of Pulsed, Inhaled Nitric Oxide (iNO) In Subjects With World Health Organization (WHO) Group 3 Pulmonary Hypertension (PH) Associated With Chronic Obstructive Pulmonary Disease (COPD) On Long Term Oxygen Therapy (LTOT) INHALE 1

Conditions
-----------------
Pulmonary Hypertension, Chronic Obstructive Pulmonary Disease

Intervention / Treatment
-----------------
* Combination Product: Inhaled NO delivered via INOpulse DS-C Device
* Combination Product: Placebo delivered via INOpulse DS-C Device


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 Age ≥ 40 years, ≤ 80 years A confirmed diagnosis of COPD by the Global initiative for chronic Obstructive Lung Disease (GOLD) criteria 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 prior to screening can be used unless obtained within ± 7 days of an exacerbation; otherwise, the test must be performed during screening) Receiving LTOT for ≥ 3 months and ≥ 10 hours per day as determined by history Echocardiogram with technical adequacy demonstrating tricuspid regurgitation velocity (TRV) ≥ 2.9 m/s at Screening, as determined by a blinded central echocardiography laboratory Females of childbearing potential must have a negative pre-treatment urine pregnancy test 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: Positive urine cotinine test Currently using, or having used within the past month, a nicotine patch A diagnosis of asthma or other non-COPD respiratory disease, in the opinion of the Investigator Lack of patency of nares upon physical examination Experienced an exacerbation requiring start of or increase in systemic oral corticosteroid therapy and/or hospitalization during the last month (ATS COPD Guidelines 2004) Left ventricular dysfunction as measured by: Screening echocardiographic evidence of left ventricular systolic dysfunction (left ventricular ejection fraction (LVEF) < 40%), or Screening echocardiographic evidence of left ventricular diastolic dysfunction > moderate (i.e., > Grade 2), or 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 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 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) Use of investigational drugs or devices within 30 days prior to enrollment into the study Any underlying medical or psychiatric condition that, in the opinion of the Investigator, makes the subject an unsuitable candidate for the study

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Inhaled NO @ 0.003 mg/kg/ ideal body weight (IBW)/hr (Part A)<br>Inhaled NO using 3.0 mg/L [2440 ppm] NO minicylinder delivered via INOpulse® DS-C device | Combination Product: Inhaled NO delivered via INOpulse DS-C Device<br>* Subjects will be treated with nitric oxide by means of an INOpulse DS-C device using an INOpulse nasal cannula.<br>|
| Active Comparator: Inhaled NO @ 0.010 mg/kg/IBW/hr (Part A)<br>Inhaled NO using 3.0 mg/L [2440 ppm] NO minicylinder delivered via INOpulse® DS-C device | Combination Product: Inhaled NO delivered via INOpulse DS-C Device<br>* Subjects will be treated with nitric oxide by means of an INOpulse DS-C device using an INOpulse nasal cannula.<br>|
| Active Comparator: Inhaled NO @ 0.015 mg/kg/IBW/hr (Part A)<br>Inhaled NO using 6.0 mg/L [4880 ppm] NO minicylinder delivered via INOpulse® DS-C device | Combination Product: Inhaled NO delivered via INOpulse DS-C Device<br>* Subjects will be treated with nitric oxide by means of an INOpulse DS-C device using an INOpulse nasal cannula.<br>|
| Placebo Comparator: Placebo random @ 0.003, 0.010 or 0.015 mg/kg/IBW/hr (Part A)<br>Placebo using 99.999% N2 minicylinder delivered via INOpulse® DS-C device | Combination Product: Placebo delivered via INOpulse DS-C Device<br>* Subjects will be treated with nitrogen gas by means of an INOpulse DS-C device using an INOpulse nasal cannula.<br>|
| Active Comparator: Inhaled NO @ 0.030 mg/kg IBW/hr (Part B)<br>Inhaled NO using 6.0 mg/L [4880 ppm] NO minicylinder delivered via INOpulse® DS-C device | Combination Product: Inhaled NO delivered via INOpulse DS-C Device<br>* Subjects will be treated with nitric oxide by means of an INOpulse DS-C device using an INOpulse nasal cannula.<br>|
| Active Comparator: Inhaled NO @ 0.075 mg/kg IBW/hr (Part B)<br>Inhaled NO using 6.0 mg/L [4880 ppm] NO minicylinder delivered via INOpulse® DS-C device | Combination Product: Inhaled NO delivered via INOpulse DS-C Device<br>* Subjects will be treated with nitric oxide by means of an INOpulse DS-C device using an INOpulse nasal cannula.<br>|
| Active Comparator: Placebo random @ 0.030 or 0.075 mg/kg/IBW (Part B)<br>Placebo using 99.999% N2 minicylinder delivered via INOpulse® DS-C device | Combination Product: Placebo delivered via INOpulse DS-C Device<br>* Subjects will be treated with nitrogen gas by means of an INOpulse DS-C device using an INOpulse nasal cannula.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pulmonary arterial systolic pressure (PASP) from Baseline after treatment with iNO (measured by 2D transthoracic echocardiography with Doppler) |  | baseline to end of treatment (1 day) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The secondary outcome is the occurrence of a decrease ≥ 5 mm Hg of partial pressure of oxygen in arterial blood (PaO2) from Baseline after treatment with iNO |  | baseline to end of treatment (1 day) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Long term oxygen therapy (LTOT), Inhaled nitric oxide (iNO), Pulmonary hypertension (PH), Chronic obstructive pulmonary disease (COPD)