Inhaled Nitric Oxide/INOpulse DS for Pulmonary Arterial Hypertension (PAH)

NCT01457781 | Completed Phase 2 DMC

• 1 other identifier: IK-7001-PAH-201
• Study Type: interventional
• Target: 80
• Locations: 2 countries
• Sites: 51

Brief Summary

This is a Phase 2, Placebo Controlled, Double-Blind, Randomized, Clinical Study to Determine Safety, Tolerability and Efficacy of Pulsed, Inhaled Nitric Oxide (iNO) Versus Placebo as Add-on Therapy in Symptomatic Subjects with Pulmonary Arterial Hypertension (PAH).

Conditions

Pulmonary Arterial Hypertension; Pulmonary Hypertension

Keywords

Inhaled nitric oxide; pulmonary arterial hypertension; pulmonary hypertension; PAH

Outcome Measures

Primary Outcomes (1)

• The primary endpoint is change in pulmonary vascular resistance (PVR) (dynes. sec/cm-5) from baseline to EOS Part 1.

  Change from Baseline to 18 weeks in PVR

  baseline to Week 16

Secondary Outcomes (5)

• Change in 6 minute walk distance (6MWD) from baseline to EOS Part 1

  baseline to Week 16

• Time (in days) to first clinical worsening event (TTCW) from randomization to EOS Part 1

  randomization to Week 16

• Change in World Health Organization (WHO) Functional Class from baseline to EOS Part 1

  baseline to Week 16

• Change in Borg Dyspnea Score (BDS) from baseline to EOS Part 1

  baseline to Week 16

• Change in patient reported outcome (PRO) scores by the SF-36 short form version 2 and the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) from baseline to EOS Part 1

  baseline to Week 16

Study Arms (3)

0.025 mg inhaled nitric oxide

ACTIVE COMPARATOR

Inhaled nitric oxide (iNO) 0.025 mg/kg IBW/hr for up to 24 hours/day x 16 weeks (3.0 mg/L \[2440 ppm\] NO mini-cylinder; change q 24 hours) delivered via INOpulse® DS delivery device.

Combination Product: Inhaled Nitric Oxide 0.025 mg/kg IBW/hr delivered via INOpulse DS Device

0.075 mg inhaled nitric oxide

ACTIVE COMPARATOR

Inhaled nitric oxide (iNO) 0.075 mg/kg IBW/hr for up to 24 hours/day x 16 weeks (6.0 mg/L \[4880 ppm\] NO mini-cylinder; change q 24 hours) delivered via INOpulse® DS delivery device.

Combination Product: Inhaled nitric oxide 0.075 mg/kg IBW/hr delivered via INOpulse DS Device

placebo

PLACEBO COMPARATOR

Placebo 0.075 mg/kg IBW/hr for up to 24 hours/day x 16 weeks\* (99.999% Nitrogen \[N2\] mini-cylinder; change q 24 hours) delivered via INOpulse® DS delivery device.

Combination Product: Placebo delivered via INOpulse DS Device

Interventions

Inhaled Nitric Oxide 0.025 mg/kg IBW/hr delivered via INOpulse DS Device COMBINATION_PRODUCT

Cohort 1: 0.025 mg/kg IBW/hr for up to 24 hours/day x 16 weeks (3.0 mg/L \[2440 ppm\] NO mini-cylinder; change q 24 hours) delivered via INOpulse DS Device and INOpulse DS nasal cannula

0.025 mg inhaled nitric oxide

Placebo delivered via INOpulse DS Device COMBINATION_PRODUCT

Placebo 0.075 mg/kg IBW/hr for up to 24 hours/day x 16 weeks (Nitrogen N2, 99.999%) delivered via INOpulse DS Device and INOpulse DS nasal cannula

placebo

Inhaled nitric oxide 0.075 mg/kg IBW/hr delivered via INOpulse DS Device COMBINATION_PRODUCT

Cohort 2: 0.075 mg/kg IBW/hr for up to 24 hours/day x 16 weeks (6.0 mg/L \[4880 ppm\] NO mini-cylinder; change q 24 hours) delivered via INOpulse DS Device and INOpulse DS nasal cannula

0.075 mg inhaled nitric oxide

Eligibility Criteria

• Age: 16 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent form (ICF) (and assent as appropriate) prior to the initiation of any study mandated procedures or assessments
• A confirmed diagnosis of Pulmonary Hypertension Group 1 (PAH) who have either idiopathic PAH (IPAH), heritable PAH, anorexigen-induced PAH, associated PAH (APAH) with connective tissue disease (CTD), APAH with repaired simple congenital systemic to pulmonary shunt (i.e., atrial septal defect \[ASD\], ventricular septal defect \[VSD\] and/or patent ductus arteriosus \[PDA\]; complete repair at least 1 year prior to Screening) or APAH with human immunodeficiency virus (HIV)
• Confirmation of PAH diagnosis at the time of Baseline RHC according to the following definition: mPAP ≥ 25 mmHg at rest, with a concomitant mean pulmonary capillary wedge pressure (mPCWP), mean left atrial pressure (mLAP), or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg and a PVR ≥ 240 dynes.sec/cm-5
• MWD at least 100 meters and no greater than 450 meters
• The subject is receiving at least one approved PAH therapy and is clinically symptomatic from PAH (e.g., onset or increased dyspnea on exertion, dizziness, near-syncope, syncope, chest pain or peripheral edema)
• Background PAH medication doses (including calcium channel blockade if being used to treat PAH) must be stable for at least 12 weeks prior to Screening
• If on background conventional therapy (e.g., digoxin, diuretics, supplemental oxygen, anticoagulation), it must have been started at least 30 days prior to Screening and be on a stable dose for at least 30 days except for anticoagulation dose
• Age between 16 and 80 years (inclusive)
• Male height ≤ 200 cm (6'7") or Female height ≤ 210 cm (6'11")
• Subjects are willing and considered in the judgment of the Investigator able to use the INOpulse DS device continuously for up to 24 hours per day
• Females of childbearing potential must have a negative pre-treatment serum pregnancy test and must be on a reliable method of contraception (including double protection if appropriate, e.g., for subjects concurrently treated with bosentan therapy)

You may not qualify if:

• Subjects with known HIV infection within the past 2 years who have a history of or show any clinical or laboratory evidence of any opportunistic pulmonary disease (e.g., tuberculosis, Pneumocystis carinii pneumonia, or other pneumonias) at the time of Screening
• PAH associated with portal hypertension, untreated thyroid disorders, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy
• PAH associated with significant venous or capillary involvement (PCWP \> 15 mmHg), known pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis
• Any subject with WHO PH Groups 2, 3, 4 or 5
• Left ventricular systolic dysfunction, i.e., left ventricular ejection fraction (LVEF) \< 40% or left ventricular shortening fraction (LVSF) \< 22%
• Left ventricular diastolic dysfunction, i.e., PCWP \> 15 mmHg at rest or with exercise, acute volume loading or pharmacologic testing
• History of clinically significant cardiomyopathy or valvular heart disease (i.e., moderate or greater aortic insufficiency; moderate or greater aortic stenosis; or moderate or greater mitral valve disease)
• Clinically significant cardiac ischemic disease requiring use of nitrates, or hospital admission for acute coronary syndrome or intervention (percutaneous coronary intervention, coronary artery stent, coronary artery bypass surgery) within the past 90 days
• Down syndrome
• Any subject who develops a PCWP \> 20 mmHg during AVT with iNO
• Systemic hypertension defined as systolic blood pressure (SBP) \> 160 mmHg and/or diastolic blood pressure (DBP) \> 100 mmHg persistent at Screening after a period of rest (treated or untreated)
• Systemic hypotension defined as SBP \< 90 mmHg persistent at Screening after a period of rest
• Moderate to severe obstructive lung disease defined as both a forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) \< 70% and FEV1 \< 65% of predicted value (bronchodilator administration prior to testing is optional; the test should be done within 3 years for all subjects with the exception of APAH/CTD which needs to be done within 6 months prior to Screening)
• Moderate to severe restrictive lung disease: total lung capacity (TLC) \< 60% of predicted; if TLC 60% to 70% predicted, a high resolution CT scan showing diffuse disease or more than mild patchy disease (done within 3 years for all subjects with the exception of APAH/CTD which needs to be done within 6 months prior to Screening)
• Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C

Sponsors & Collaborators

• Bellerophon Pulse Technologies: lead

Study Sites (51)

University of Alabama at Birmingham

Birmingham, Alabama, 35294-0006, United States

Location

Arizona Pulmonary Specialists

Phoenix, Arizona, 85012, United States

Location

Allianz Research Institute, Inc.

Fountain Valley, California, 92708, United States

Location

University of California, San Francisco-Fresno

Fresno, California, 93721, United States

Location

West Los Angeles VA Healthcare Center

Los Angeles, California, 90073, United States

Location

David Geffen School of Medicine at UCLA

Los Angeles, California, 90095, United States

Location

Los Angeles Biomedical Research Institute at Harbor-UCLA Med Ctr

Torrance, California, 90509, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

University of Colorado Denver

Aurora, Colorado, 80045, United States

Location

South Denver Cardiology Associates P.C.

Littleton, Colorado, 80120, United States

Location

Christiana Care Health System

Newark, Delaware, 19713, United States

Location

University of Florida College of Medicine

Jacksonville, Florida, 32209, United States

Location

Cleveland Clinic Florida

Weston, Florida, 33331, United States

Location

Emory University Hospital-Emory Clinic

Atlanta, Georgia, 30322, United States

Location

University of Iowa Hospitals & Clinics

Iowa City, Iowa, 52242, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

University of Kentucky Gill Heart

Lexington, Kentucky, 40536, United States

Location

Kentuckiana Pulmonary Associates

Louisville, Kentucky, 40202, United States

Location

LSUHSC-New Orleans

New Orleans, Louisiana, 70112, United States

Location

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Boston University Medical Center/Boston University School of Medicine

Boston, Massachusetts, 02118-2526, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

University of Minnesota, Cardiovascular Division

Minneapolis, Minnesota, 55455, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

University of Medicine and Dentistry of NJ

Newark, New Jersey, 07103, United States

Location

Barnabas Health Newark Beth Israel Medical Center

Newark, New Jersey, 07112, United States

Location

Beth Israel Medical Center

New York, New York, 10003, United States

Location

Weill Cornell Medical Center

New York, New York, 10021, United States

Location

Montefiore Medical Center

The Bronx, New York, 10461, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

UC Health/University of Cincinnati

Cincinnati, Ohio, 45267, United States

Location

University Hospitals Case Medical Center

Cleveland, Ohio, 44106, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Ohio State University Martha Morehouse Medical Pavillion

Columbus, Ohio, 43221, United States

Location

South Oklahoma Heart Research LLC

Oklahoma City, Oklahoma, 73135, United States

Location

Legacy Medical Group - Pulmonary Clinic

Portland, Oregon, 97210, United States

Location

Temple University Hospital

Philadelphia, Pennsylvania, 19140, United States

Location

Allegheny Singer Research Institute/Allegheny General Hospital

Pittsburgh, Pennsylvania, 15212, United States

Location

Rhode Island Hospital

Providence, Rhode Island, 02903, United States

Location

Sioux Falls Cardiovascular PC

Sioux Falls, South Dakota, 57108, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Intermountain Medical Center

Murray, Utah, 84157, United States

Location

Aurora St. Luke's Medical Center

Milwaukee, Wisconsin, 53215, United States

Location

Peter Lougheed Center

Calgary, Alberta, T1Y614, Canada

Location

ABACUS - University of Alberta Hospitals

Edmonton, Alberta, T6G 2B7, Canada

Location

London Health Sciences Centre

London, Ontario, N6A 5W9, Canada

Location

University Health Network - Toronto General Hospital

Toronto, Ontario, M5G 2C4, Canada

Location

MeSH Terms

Conditions

Pulmonary Arterial Hypertension; Hypertension, Pulmonary

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Ashika Ahmed, MD

  Bellerophon Therapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 12, 2011
• First Posted: October 24, 2011
• Study Start: April 1, 2012
• Primary Completion: October 1, 2014
• Study Completion: July 1, 2016
• Last Updated: February 27, 2023

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

CA (4); US (47)