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

Sponsor

Bellerophon Pulse Technologies (Industry)

Overall Status

Completed

CT.gov ID

NCT01728220

Collaborator

(none)

159

Enrollment

Locations

Arms

Duration (Months)

3.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Hypertension Chronic Obstructive Pulmonary Disease	Combination Product: Inhaled NO delivered via INOpulse DS-C Device Combination Product: Placebo delivered via INOpulse DS-C Device	Phase 2

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

Study Design

Study Type:

Interventional

Actual Enrollment :

159 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Study Start Date :

Dec 1, 2012

Actual Primary Completion Date :

Jun 1, 2014

Actual Study Completion Date :

Jul 1, 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

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

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)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Jasper Summit Research LLC	Jasper	Alabama	United States	35501
2	Clinical Trial Connection	Flagstaff	Arizona	United States	86001
3	Pulmonary Associates P.A.	Phoenix	Arizona	United States	85006
4	Radin Cardiovascular Medical Associates	Newport Beach	California	United States	92663
5	Western Connecticut Medical Group PC	Danbury	Connecticut	United States	06810
6	Waterbury Pulmonary Associates	Waterbury	Connecticut	United States	06708
7	Bay Area Chest Physicians	Clearwater	Florida	United States	33756
8	Gary J. Richmond, MD, PA	Fort Lauderdale	Florida	United States	33316
9	East Coast Institute for Research	Jacksonville	Florida	United States	32204
10	Pulmonary Disease Specialists PA	Kissimmee	Florida	United States	34741
11	San Marcus Research Clinic Inc.	Miami	Florida	United States	33015
12	St. Paul Medical Research Center Inc.	Miami	Florida	United States	33126
13	IMIC, Inc.	Miami	Florida	United States	33140
14	Elite Clinical Research	Miami	Florida	United States	33144
15	South Florida Research Phase I-IV	Miami	Florida	United States	33165
16	Health & Life Research Solutions Inc.	Miami	Florida	United States	33173
17	Advanced Research Institute, Inc.	New Port Richey	Florida	United States	34653
18	Central Florida Pulmonary Group, P.A.	Orlando	Florida	United States	32803
19	Research Alliance	Saint Petersburg	Florida	United States	33710
20	Bassette Medical Research Inc.	Sebring	Florida	United States	33872
21	Concept Clinical Trials, LLC	Tamarac	Florida	United States	33319
22	Axcess Medical Research	Wellington	Florida	United States	33414
23	Florida Premier Research Institute	Winter Park	Florida	United States	32789
24	River Birch Research Alliance LLC	Blue Ridge	Georgia	United States	30513
25	Medical Associates of North Georgia	Canton	Georgia	United States	30114
26	Veritas Clinical Specialties, Ltd	Topeka	Kansas	United States	66606
27	Graves-Gilbert Clinic	Bowling Green	Kentucky	United States	42101
28	Kentucky Research Group	Louisville	Kentucky	United States	40218
29	MedPharmics LLC	Metairie	Louisiana	United States	70006
30	Physician HealthCare Network, PC	Port Huron	Michigan	United States	48060
31	Montefiore Medical Center-Weiler Division	Bronx	New York	United States	10461
32	American Health Research	Charlotte	North Carolina	United States	28207
33	University Hospitals Case Medical Center	Cleveland	Ohio	United States	44106
34	Temple Lung Center Pulmonary & Critical Care Medicine	Philadelphia	Pennsylvania	United States	19140
35	Lowcountry Lung and Critical Care	Charleston	South Carolina	United States	29406
36	Neem Research Group Inc	Columbia	South Carolina	United States	29201
37	Gaffney Pharmaceutical Research	Gaffney	South Carolina	United States	29340
38	Greenville Pharmaceutical Research	Greenville	South Carolina	United States	29615
39	Clinical Research of Rock Hill	Rock Hill	South Carolina	United States	29732
40	Spartanburg Medical Research	Spartanburg	South Carolina	United States	29303
41	Pioneer Research Solutions, Inc.	Sugar Land	Texas	United States	77479
42	Pulmonary Associates of Richmond Inc	Richmond	Virginia	United States	23225
43	Zain Research LLC	Richland	Washington	United States	99352