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

Phase 2

Completed

Conditions: Chronic Obstructive Pulmonary Disease
Pulmonary Hypertension

Interventions: Combination Product: Placebo delivered via INOpulse DS-C Device
Combination Product: Inhaled NO delivered via INOpulse DS-C Device

Registration Number: NCT01728220

Lead Sponsor: Bellerophon Pulse Technologies

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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 159

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:
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
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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo random @ 0.003, 0.010 or 0.015 mg/kg/IBW/hr (Part A)	Placebo delivered via INOpulse DS-C Device	Placebo using 99.999% N2 minicylinder delivered via INOpulse® DS-C device
Inhaled NO @ 0.075 mg/kg IBW/hr (Part B)	Inhaled NO delivered via INOpulse DS-C Device	Inhaled NO using 6.0 mg/L \[4880 ppm\] NO minicylinder delivered via INOpulse® DS-C device
Inhaled NO @ 0.015 mg/kg/IBW/hr (Part A)	Inhaled NO delivered via INOpulse DS-C Device	Inhaled NO using 6.0 mg/L \[4880 ppm\] NO minicylinder delivered via INOpulse® DS-C device
Inhaled NO @ 0.003 mg/kg/ ideal body weight (IBW)/hr (Part A)	Inhaled NO delivered via INOpulse DS-C Device	Inhaled NO using 3.0 mg/L \[2440 ppm\] NO minicylinder delivered via INOpulse® DS-C device
Inhaled NO @ 0.010 mg/kg/IBW/hr (Part A)	Inhaled NO delivered via INOpulse DS-C Device	Inhaled NO using 3.0 mg/L \[2440 ppm\] NO minicylinder delivered via INOpulse® DS-C device
Inhaled NO @ 0.030 mg/kg IBW/hr (Part B)	Inhaled NO delivered via INOpulse DS-C Device	Inhaled NO using 6.0 mg/L \[4880 ppm\] NO minicylinder delivered via INOpulse® DS-C device
Placebo random @ 0.030 or 0.075 mg/kg/IBW (Part B)	Placebo delivered via INOpulse DS-C Device	Placebo using 99.999% N2 minicylinder delivered via INOpulse® DS-C device

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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)

Trial Locations

Locations (43): Pulmonary Disease Specialists PA
🇺🇸
Kissimmee, Florida, United States
River Birch Research Alliance LLC
🇺🇸
Blue Ridge, Georgia, United States
Western Connecticut Medical Group PC
🇺🇸
Danbury, Connecticut, United States
Spartanburg Medical Research
🇺🇸
Spartanburg, South Carolina, United States
Elite Clinical Research
🇺🇸
Miami, Florida, United States
South Florida Research Phase I-IV
🇺🇸
Miami, Florida, United States
Clinical Trial Connection
🇺🇸
Flagstaff, Arizona, United States
Bassette Medical Research Inc.
🇺🇸
Sebring, Florida, United States
Waterbury Pulmonary Associates
🇺🇸
Waterbury, Connecticut, United States
Research Alliance
🇺🇸
Saint Petersburg, Florida, United States
Jasper Summit Research LLC
🇺🇸
Jasper, Alabama, United States
Bay Area Chest Physicians
🇺🇸
Clearwater, Florida, United States
Radin Cardiovascular Medical Associates
🇺🇸
Newport Beach, California, United States
IMIC, Inc.
🇺🇸
Miami, Florida, United States
Physician HealthCare Network, PC
🇺🇸
Port Huron, Michigan, United States
East Coast Institute for Research
🇺🇸
Jacksonville, Florida, United States
Concept Clinical Trials, LLC
🇺🇸
Tamarac, Florida, United States
Central Florida Pulmonary Group, P.A.
🇺🇸
Orlando, Florida, United States
Axcess Medical Research
🇺🇸
Wellington, Florida, United States
Medical Associates of North Georgia
🇺🇸
Canton, Georgia, United States
Kentucky Research Group
🇺🇸
Louisville, Kentucky, United States
University Hospitals Case Medical Center
🇺🇸
Cleveland, Ohio, United States
Lowcountry Lung and Critical Care
🇺🇸
Charleston, South Carolina, United States
Temple Lung Center Pulmonary & Critical Care Medicine
🇺🇸
Philadelphia, Pennsylvania, United States
Gaffney Pharmaceutical Research
🇺🇸
Gaffney, South Carolina, United States
Greenville Pharmaceutical Research
🇺🇸
Greenville, South Carolina, United States
Pulmonary Associates of Richmond Inc
🇺🇸
Richmond, Virginia, United States
Clinical Research of Rock Hill
🇺🇸
Rock Hill, South Carolina, United States
Zain Research LLC
🇺🇸
Richland, Washington, United States
Health & Life Research Solutions Inc.
🇺🇸
Miami, Florida, United States
Advanced Research Institute, Inc.
🇺🇸
New Port Richey, Florida, United States
Florida Premier Research Institute
🇺🇸
Winter Park, Florida, United States
Pulmonary Associates P.A.
🇺🇸
Phoenix, Arizona, United States
Gary J. Richmond, MD, PA
🇺🇸
Fort Lauderdale, Florida, United States
St. Paul Medical Research Center Inc.
🇺🇸
Miami, Florida, United States
San Marcus Research Clinic Inc.
🇺🇸
Miami, Florida, United States
Veritas Clinical Specialties, Ltd
🇺🇸
Topeka, Kansas, United States
MedPharmics LLC
🇺🇸
Metairie, Louisiana, United States
Graves-Gilbert Clinic
🇺🇸
Bowling Green, Kentucky, United States
Neem Research Group Inc
🇺🇸
Columbia, South Carolina, United States
Pioneer Research Solutions, Inc.
🇺🇸
Sugar Land, Texas, United States
Montefiore Medical Center-Weiler Division
🇺🇸
Bronx, New York, United States
American Health Research
🇺🇸
Charlotte, North Carolina, United States