Clinical trial NCT01728220: Two-Part Dose-Confirming Study of Pulsed Inhaled Nitric Oxide in Subjects With WHO Group 3 Pulmonary Hypertension Associated With COPD
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Hypertension
Chronic Obstructive Pulmonary Disease
Keywords: Inhaled nitric oxide (iNO)
Pulmonary hypertension (PH)
Chronic obstructive pulmonary disease (COPD)
Long term oxygen therapy (LTOT)
Lead sponsor: Bellerophon
Sponsor class: INDUSTRY
First posted: 2012-11-19
Enrollment: 159
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: Inclusion Criteria:

1. 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
2. Age ≥ 40 years, ≤ 80 years
3. A confirmed diagnosis of COPD by the Global initiative for chronic Obstructive Lung Disease (GOLD) criteria
4. 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)
5. Receiving LTOT for ≥ 3 months and ≥ 10 hours per day as determined by history
6. Echocardiogram with technical adequacy demonstrating tricuspid regurgitation velocity (TRV) ≥ 2.9 m/s at Screening, as determined by a blinded central echocardiography laboratory
7. Females of childbearing potential must have a negative pre-treatment urine pregnancy test
8. 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:

1. Positive urine cotinine test
2. Currently using, or having used within the past month, a nicotine patch
3. A diagnosis of asthma or other non-COPD respiratory disease, in the opinion of the Investigator
4. Lack of patency of nares upon physical examination
5. Experienced an exacerbation requiring start of or increase in systemic oral corticosteroid therapy and/or hospitalization during the last month (ATS COPD Guidelines 2004)
6. 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
7. 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
8. 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)
9. Use of investigational drugs or devices within 30 days prior to enrollment into the study
10. Any underlying medical or psychiatric condition that, in the opinion of the Investigator, makes the subject an unsuitable candidate for the study

Primary outcomes:
measure: Change in pulmonary arterial systolic pressure (PASP) from Baseline after treatment with iNO (measured by 2D transthoracic echocardiography with Doppler)
timeFrame: baseline to end of treatment (1 day)
Secondary outcomes:
measure: 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
timeFrame: baseline to end of treatment (1 day)
Other outcomes:
Locations:
city: Jasper
country: United States
facility: Jasper Summit Research LLC
state: Alabama
city: Flagstaff
country: United States
facility: Clinical Trial Connection
state: Arizona
city: Phoenix
country: United States
facility: Pulmonary Associates P.A.
state: Arizona
city: Newport Beach
country: United States
facility: Radin Cardiovascular Medical Associates
state: California
city: Danbury
country: United States
facility: Western Connecticut Medical Group PC
state: Connecticut
city: Waterbury
country: United States
facility: Waterbury Pulmonary Associates
state: Connecticut
city: Clearwater
country: United States
facility: Bay Area Chest Physicians
state: Florida
city: Fort Lauderdale
country: United States
facility: Gary J. Richmond, MD, PA
state: Florida
city: Jacksonville
country: United States
facility: East Coast Institute for Research
state: Florida
city: Kissimmee
country: United States
facility: Pulmonary Disease Specialists PA
state: Florida
city: Miami
country: United States
facility: San Marcus Research Clinic Inc.
state: Florida
city: Miami
country: United States
facility: St. Paul Medical Research Center Inc.
state: Florida
city: Miami
country: United States
facility: IMIC, Inc.
state: Florida
city: Miami
country: United States
facility: Elite Clinical Research
state: Florida
city: Miami
country: United States
facility: South Florida Research Phase I-IV
state: Florida
city: Miami
country: United States
facility: Health & Life Research Solutions Inc.
state: Florida
city: New Port Richey
country: United States
facility: Advanced Research Institute, Inc.
state: Florida
city: Orlando
country: United States
facility: Central Florida Pulmonary Group, P.A.
state: Florida
city: Saint Petersburg
country: United States
facility: Research Alliance
state: Florida
city: Sebring
country: United States
facility: Bassette Medical Research Inc.
state: Florida
city: Tamarac
country: United States
facility: Concept Clinical Trials, LLC
state: Florida
city: Wellington
country: United States
facility: Axcess Medical Research
state: Florida
city: Winter Park
country: United States
facility: Florida Premier Research Institute
state: Florida
city: Blue Ridge
country: United States
facility: River Birch Research Alliance LLC
state: Georgia
city: Canton
country: United States
facility: Medical Associates of North Georgia
state: Georgia
city: Topeka
country: United States
facility: Veritas Clinical Specialties, Ltd
state: Kansas
city: Bowling Green
country: United States
facility: Graves-Gilbert Clinic
state: Kentucky
city: Louisville
country: United States
facility: Kentucky Research Group
state: Kentucky
city: Metairie
country: United States
facility: MedPharmics LLC
state: Louisiana
city: Port Huron
country: United States
facility: Physician HealthCare Network, PC
state: Michigan
city: Bronx
country: United States
facility: Montefiore Medical Center-Weiler Division
state: New York
city: Charlotte
country: United States
facility: American Health Research
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Temple Lung Center Pulmonary & Critical Care Medicine
state: Pennsylvania
city: Charleston
country: United States
facility: Lowcountry Lung and Critical Care
state: South Carolina
city: Columbia
country: United States
facility: Neem Research Group Inc
state: South Carolina
city: Gaffney
country: United States
facility: Gaffney Pharmaceutical Research
state: South Carolina
city: Greenville
country: United States
facility: Greenville Pharmaceutical Research
state: South Carolina
city: Rock Hill
country: United States
facility: Clinical Research of Rock Hill
state: South Carolina
city: Spartanburg
country: United States
facility: Spartanburg Medical Research
state: South Carolina
city: Sugar Land
country: United States
facility: Pioneer Research Solutions, Inc.
state: Texas
city: Richmond
country: United States
facility: Pulmonary Associates of Richmond Inc
state: Virginia
city: Richland
country: United States
facility: Zain Research LLC
state: Washington
Study officials:
affiliation: Bellerophon Therapeutics
name: Ashika Ahmed, MD
role: STUDY_DIRECTOR
References: