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

Information source: Bellerophon
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Pulmonary Arterial Hypertension; Pulmonary Hypertension

Intervention: Nitric Oxide (Drug); Placebo (Other); Nitric Oxide (Drug)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: Bellerophon Pulse Technologies

Official(s) and/or principal investigator(s):
Stephen Haworth, MB, MRCP, Study Director, Affiliation: Bellerophon Therapeutics (consultant)


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).

Clinical Details

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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

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

Secondary outcome:

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

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

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

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

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

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.


Minimum age: 16 Years. Maximum age: 80 Years. Gender(s): Both.


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

Locations and Contacts

University of Alabama at Birmingham, Birmingham, Alabama 35294-0006, United States

Peter Lougheed Center, Calgary, Alberta T1Y614, Canada

ABACUS - University of Alberta Hospitals, Edmonton, Alberta T6G 2B7, Canada

Arizona Pulmonary Specialists, Phoenix, Arizona 85012, United States

Allianz Research Institute, Inc., Fountain Valley, California 92708, United States

University of California, San Francisco-Fresno, Fresno, California 93721, United States

David Geffen School of Medicine at UCLA, Los Angeles, California 90095, United States

West Los Angeles VA Healthcare Center, Los Angeles, California 90073, United States

Los Angeles Biomedical Research Institute at Harbor-UCLA Med Ctr, Torrance, California 90509, United States

Children's Hospital Colorado, Aurora, Colorado 80045, United States

University of Colorado Denver, Aurora, Colorado 80045, United States

South Denver Cardiology Associates P.C., Littleton, Colorado 80120, United States

Christiana Care Health System, Newark, Delaware 19713, United States

University of Florida College of Medicine, Jacksonville, Florida 32209, United States

Cleveland Clinic Florida, Weston, Florida 33331, United States

Emory University Hospital-Emory Clinic, Atlanta, Georgia 30322, United States

University of Iowa Hospitals & Clinics, Iowa City, Iowa 52242, United States

University of Kansas Medical Center, Kansas City, Kansas 66160, United States

University of Kentucky Gill Heart, Lexington, Kentucky 40536, United States

Kentuckiana Pulmonary Associates, Louisville, Kentucky 40202, United States

LSUHSC-New Orleans, New Orleans, Louisiana 70112, United States

University of Maryland Medical Center, Baltimore, Maryland 21201, United States

Boston University Medical Center/Boston University School of Medicine, Boston, Massachusetts 02118-2526, United States

Tufts Medical Center, Boston, Massachusetts 02111, United States

University of Michigan, Ann Arbor, Michigan 48109, United States

University of Minnesota, Cardiovascular Division, Minneapolis, Minnesota 55455, United States

Mayo Clinic, Rochester, Minnesota 55905, United States

Washington University School of Medicine, St. Louis, Missouri 63110, United States

Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, United States

Barnabas Health Newark Beth Israel Medical Center, Newark, New Jersey 07112, United States

University of Medicine and Dentistry of NJ, Newark, New Jersey 07103, United States

Montefiore Medical Center, Bronx, New York 10461, United States

Beth Israel Medical Center, New York, New York 10003, United States

Weill Cornell Medical Center, New York, New York 10021, United States

Duke University Medical Center, Durham, North Carolina 27710, United States

UC Health/University of Cincinnati, Cincinnati, Ohio 45267, United States

Cleveland Clinic, Cleveland, Ohio 44195, United States

University Hospitals Case Medical Center, Cleveland, Ohio 44106, United States

Ohio State University Martha Morehouse Medical Pavillion, Columbus, Ohio 43221, United States

South Oklahoma Heart Research LLC, Oklahoma City, Oklahoma 73135, United States

London Health Sciences Centre, London, Ontario N6A 5W9, Canada

University Health Network - Toronto General Hospital, Toronto, Ontario M5G 2C4, Canada

Legacy Medical Group - Pulmonary Clinic, Portland, Oregon 97210, United States

Temple University Hospital, Philadelphia, Pennsylvania 19140, United States

Allegheny Singer Research Institute/Allegheny General Hospital, Pittsburgh, Pennsylvania 15212, United States

Rhode Island Hospital, Providence, Rhode Island 02903, United States

Sioux Falls Cardiovascular PC, Sioux Falls, South Dakota 57108, United States

University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States

Baylor College of Medicine, Houston, Texas 77030, United States

Intermountain Medical Center, Murray, Utah 84157, United States

Aurora St. Luke's Medical Center, Milwaukee, Wisconsin 53215, United States

Additional Information

Starting date: April 2012
Last updated: January 30, 2015

Page last updated: August 23, 2015

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