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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01457781
Recruitment Status : Completed
First Posted : October 24, 2011
Last Update Posted : August 4, 2016
Information provided by (Responsible Party):
Bellerophon ( Bellerophon Pulse Technologies )

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).

Condition or disease Intervention/treatment Phase
Pulmonary Arterial Hypertension Pulmonary Hypertension Drug: Nitric Oxide Other: Placebo Phase 2

Detailed Description:

Study to determine if inhaled nitric oxide (iNO) given through a special delivery device (INOpulse® DS) is safe and efficacious in treating Pulmonary Arterial Hypertension (PAH). Medical literature and clinical experience suggests that iNO at pulsed doses of 0.013 to 0.1 mg/kg per hour for 1 month to 2+ years appears safe and suggests efficacy for the treatment of pulmonary hypertension.

There are two parts to this study. In Part 1 (week 0 to week 16), the objectives are to determine the safety, tolerability, efficacy, and exploratory objectives of two different doses of iNO delivered by a pulsed delivery device in symptomatic subjects with PAH who remain symptomatic due to PAH on approved PAH monotherapy or combination approved PAH therapy. In Part 2 (week 17 to end of study Part 2 [EOS Part 2]), the objective is to compile data on the long-term effects of iNO on safety, tolerability, clinical and hemodynamic measures.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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)
Study Start Date : April 2012
Actual Primary Completion Date : October 2014
Actual Study Completion Date : July 2016

Arm Intervention/treatment
Active Comparator: 0.025 mg inhaled nitric oxide
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)
Drug: Nitric Oxide
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)

Active Comparator: 0.075 mg inhaled nitric oxide
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)
Drug: Nitric Oxide
Cohort 2: 0.075 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)

Placebo Comparator: placebo
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)
Other: Placebo
Placebo 0.075 mg/kg IBW/hr for up to 24 hours/day x 16 weeks (Nitrogen N2, 99.999%)

Primary Outcome Measures :
  1. The primary endpoint is change in pulmonary vascular resistance (PVR) (dynes. sec/cm-5) from baseline to EOS Part 1. [ Time Frame: baseline to Week 16 ]

Secondary Outcome Measures :
  1. Change in 6 minute walk distance (6MWD) from baseline to EOS Part 1 [ Time Frame: baseline to Week 16 ]
  2. Time (in days) to first clinical worsening event (TTCW) from randomization to EOS Part 1 [ Time Frame: randomization to Week 16 ]
  3. Change in World Health Organization (WHO) Functional Class from baseline to EOS Part 1 [ Time Frame: baseline to Week 16 ]
  4. Change in Borg Dyspnea Score (BDS) from baseline to EOS Part 1 [ Time Frame: baseline to Week 16 ]
  5. 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 [ Time Frame: baseline to Week 16 ]

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Ages Eligible for Study:   16 Years to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Signed informed consent form (ICF) (and assent as appropriate) prior to the initiation of any study mandated procedures or assessments
  2. 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)
  3. 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
  4. 6MWD at least 100 meters and no greater than 450 meters
  5. 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)
  6. 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
  7. 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
  8. If previously treated with an endothelin receptor antagonist (ERA), phosphodiesterase-5 (PDE-5) inhibitor, prostacyclin or a prostacyclin analog and is no longer on said treatment at Screening (per inclusion criteria as above), subject must have been off said treatment for > 90 days at Screening
  9. If previously treated with a calcium channel blocker as treatment for PAH and is no longer on the calcium channel blocker treatment at Screening (per inclusion criteria as above), subject must have been off the calcium channel blocker treatment for > 90 days at Screening
  10. Age between 16 and 80 years (inclusive)
  11. Male height ≤ 200 cm (6'7") or Female height ≤ 210 cm (6'11")
  12. 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
  13. 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)

Exclusion Criteria:

  1. 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
  2. PAH associated with portal hypertension, untreated thyroid disorders, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy
  3. Any subject with unrepaired congenital heart disease or repaired congenital heart disease other than the simple congenital to systemic shunts specified in the inclusion criteria, i.e., PAH associated with non-corrected simple congenital systemic-to-pulmonary shunts, corrected simple congenital systemic-to-pulmonary shunt with residual shunt post repair, or complex systemic-to- pulmonary shunts, corrected or non-corrected, or any other complex congenital heart disease, corrected or non-corrected
  4. PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), known pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis
  5. Any subject with WHO PH Groups 2, 3, 4 or 5
  6. Left ventricular systolic dysfunction, i.e., left ventricular ejection fraction (LVEF) < 40% or left ventricular shortening fraction (LVSF) < 22%
  7. Left ventricular diastolic dysfunction, i.e., PCWP > 15 mmHg at rest or with exercise, acute volume loading or pharmacologic testing
  8. 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)
  9. 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
  10. Down syndrome
  11. Any subject who develops a PCWP > 20 mmHg during AVT with iNO
  12. 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)
  13. Systemic hypotension defined as SBP < 90 mmHg persistent at Screening after a period of rest
  14. 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)
  15. 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)
  16. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
  17. Estimated creatinine clearance < 30 mL/min (Cockcroft-Gault formula)
  18. Hemoglobin < 10 gm/dL at Screening or Baseline
  19. Acute or chronic physical impairment (other than dyspnea due to PAH) that would limit the ability to comply with study procedures or adherence to therapy, including carrying and wearing the INOpulse device per study protocol
  20. Pregnant or breast-feeding at Screening
  21. Administered L-arginine within 30 days prior to Screening
  22. Known concomitant life-threatening disease with a life expectancy less than 1 year
  23. Recently started (< 12 weeks prior to randomization) or planned cardiopulmonary rehabilitation program to start within the 16 week controlled study
  24. Atrial septostomy within 3 months of randomization
  25. Any subject with PAH who is treatment naïve or receiving any unapproved therapy as their only PAH treatment (including calcium channel blockade if the calcium channel blockade is the only treatment for the PAH)
  26. Any subject who requires the use of a continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP), or other positive pressure devices to treat obstructive sleep apnea
  27. Medical problem(s) likely to preclude completion of Part 1
  28. Use of investigational drugs or devices within 30 days prior to enrollment into the study (other than acute vasodilator testing with iNO or IV epoprostenol)
  29. Any underlying medical or psychiatric condition that, in the opinion of the Investigator, makes the subject an unsuitable candidate for the study
  30. Any condition other than the subject's PAH that, in that opinion of the investigator, affects their ability to perform the 6MWT
  31. Refusal to follow the protocol, including the two RHCs in Part 1 and one RHC in Part 2
  32. Unable to travel to the investigational site for all required study visits and for all additional visits per the judgment of the Investigator or Sponsor

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01457781

  Hide Study Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294-0006
United States, Arizona
Arizona Pulmonary Specialists
Phoenix, Arizona, United States, 85012
United States, California
Allianz Research Institute, Inc.
Fountain Valley, California, United States, 92708
University of California, San Francisco-Fresno
Fresno, California, United States, 93721
West Los Angeles VA Healthcare Center
Los Angeles, California, United States, 90073
David Geffen School of Medicine at UCLA
Los Angeles, California, United States, 90095
Los Angeles Biomedical Research Institute at Harbor-UCLA Med Ctr
Torrance, California, United States, 90509
United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
University of Colorado Denver
Aurora, Colorado, United States, 80045
South Denver Cardiology Associates P.C.
Littleton, Colorado, United States, 80120
United States, Delaware
Christiana Care Health System
Newark, Delaware, United States, 19713
United States, Florida
University of Florida College of Medicine
Jacksonville, Florida, United States, 32209
Cleveland Clinic Florida
Weston, Florida, United States, 33331
United States, Georgia
Emory University Hospital-Emory Clinic
Atlanta, Georgia, United States, 30322
United States, Iowa
University of Iowa Hospitals & Clinics
Iowa City, Iowa, United States, 52242
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
United States, Kentucky
University of Kentucky Gill Heart
Lexington, Kentucky, United States, 40536
Kentuckiana Pulmonary Associates
Louisville, Kentucky, United States, 40202
United States, Louisiana
LSUHSC-New Orleans
New Orleans, Louisiana, United States, 70112
United States, Maryland
University of Maryland Medical Center
Baltimore, Maryland, United States, 21201
United States, Massachusetts
Tufts Medical Center
Boston, Massachusetts, United States, 02111
Boston University Medical Center/Boston University School of Medicine
Boston, Massachusetts, United States, 02118-2526
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
University of Minnesota, Cardiovascular Division
Minneapolis, Minnesota, United States, 55455
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, New Hampshire
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756
United States, New Jersey
University of Medicine and Dentistry of NJ
Newark, New Jersey, United States, 07103
Barnabas Health Newark Beth Israel Medical Center
Newark, New Jersey, United States, 07112
United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10461
Beth Israel Medical Center
New York, New York, United States, 10003
Weill Cornell Medical Center
New York, New York, United States, 10021
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
UC Health/University of Cincinnati
Cincinnati, Ohio, United States, 45267
University Hospitals Case Medical Center
Cleveland, Ohio, United States, 44106
Cleveland Clinic
Cleveland, Ohio, United States, 44195
Ohio State University Martha Morehouse Medical Pavillion
Columbus, Ohio, United States, 43221
United States, Oklahoma
South Oklahoma Heart Research LLC
Oklahoma City, Oklahoma, United States, 73135
United States, Oregon
Legacy Medical Group - Pulmonary Clinic
Portland, Oregon, United States, 97210
United States, Pennsylvania
Temple University Hospital
Philadelphia, Pennsylvania, United States, 19140
Allegheny Singer Research Institute/Allegheny General Hospital
Pittsburgh, Pennsylvania, United States, 15212
United States, Rhode Island
Rhode Island Hospital
Providence, Rhode Island, United States, 02903
United States, South Dakota
Sioux Falls Cardiovascular PC
Sioux Falls, South Dakota, United States, 57108
United States, Texas
University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75390
Baylor College of Medicine
Houston, Texas, United States, 77030
United States, Utah
Intermountain Medical Center
Murray, Utah, United States, 84157
United States, Wisconsin
Aurora St. Luke's Medical Center
Milwaukee, Wisconsin, United States, 53215
Canada, Alberta
Peter Lougheed Center
Calgary, Alberta, Canada, T1Y614
ABACUS - University of Alberta Hospitals
Edmonton, Alberta, Canada, T6G 2B7
Canada, Ontario
London Health Sciences Centre
London, Ontario, Canada, N6A 5W9
University Health Network - Toronto General Hospital
Toronto, Ontario, Canada, M5G 2C4
Sponsors and Collaborators
Bellerophon Pulse Technologies
Study Director: Stephen Haworth, MB, MRCP Bellerophon Therapeutics (consultant)

Responsible Party: Bellerophon Pulse Technologies Identifier: NCT01457781     History of Changes
Other Study ID Numbers: IK-7001-PAH-201
First Posted: October 24, 2011    Key Record Dates
Last Update Posted: August 4, 2016
Last Verified: August 2016

Keywords provided by Bellerophon ( Bellerophon Pulse Technologies ):
Inhaled nitric oxide
pulmonary arterial hypertension
pulmonary hypertension

Additional relevant MeSH terms:
Hypertension, Pulmonary
Familial Primary Pulmonary Hypertension
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Nitric Oxide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Protective Agents