Clinical Study of Pulsed, Inhaled Nitric Oxide Versus Placebo in Symptomatic Subjects With PAH

NCT ID: NCT02725372

Last Updated: 2023-02-21

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 207 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-04-30
• Study Completion Date: 2018-08-31

Brief Summary

Phase 3, placebo controlled, double-blind, randomized clinical study to determine safety, tolerability, and efficacy of pulsed, inhaled nitric oxide (iNO) versus placebo in symptomatic subjects with pulmonary arterial hypertension (PAH). Part 1 and Part 2

Detailed Description

Phase 3, 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 subjects with pulmonary arterial hypertension (PAH) who remain symptomatic on approved PAH monotherapy or combination approved PAH therapy and long term oxygen therapy (LTOT). (Part 1 and Part 2)

Conditions

Pulmonary Arterial Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Inhaled Nitric Oxide 75mcg/KgIBW/Hr

Part 1:

15Mcg/kg IBW/hr during Run-in Period dose titrated to Inhaled Nitric Oxide / 75mcg/KgIBW/Hr upon randomization to treatment arm.

Part 2: iNO 75 mcg/kg IBW/hr Open Label Treatment (Open Label Treatment - All Subjects)

Group Type: EXPERIMENTAL

Inhaled Nitric Oxide 75 mcg/kg IBW/hr

Intervention Type: DRUG

Inhaled Nitric Oxide 15mcg/Kg IBW/hr for two week run in period dose titrated to Inhaled Nitric Oxide 75 mcg/kg IBW/hr at randomizationTreatment Period (Week 3 to Week 18)

Placebo

Part 1:

Placebo dose setting 15mcg/kg IBW/hr Run In Period / Placebo dose setting 75 mcg/kg IBW/hr treatment period

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Part 1 Placebo arm: Inhaled Nitric Oxide 15mcg/Kg IBW/hrfor two week run in period dose titrated to Inhaled Nitric Oxide 75 mcg/kg IBW/hr at randomizationTreatment Period

Interventions

Inhaled Nitric Oxide 75 mcg/kg IBW/hr

Inhaled Nitric Oxide 15mcg/Kg IBW/hr for two week run in period dose titrated to Inhaled Nitric Oxide 75 mcg/kg IBW/hr at randomizationTreatment Period (Week 3 to Week 18)

Intervention Type: DRUG

Placebo

Part 1 Placebo arm: Inhaled Nitric Oxide 15mcg/Kg IBW/hrfor two week run in period dose titrated to Inhaled Nitric Oxide 75 mcg/kg IBW/hr at randomizationTreatment Period

Intervention Type: DRUG

Other Intervention Names

Inhaled Nitric Oxide; iNO; Inhaled Nitric Oxide; iNO

Eligibility Criteria

Inclusion Criteria

1. Signed Informed Consent Form (and assent as appropriate) prior to the initiation of any study mandated procedures or assessments

2. A confirmed diagnosis of PAH Group 1 who have either idiopathic PAH (IPAH), heritable PAH, drug and toxin-induced PAH, associated PAH (APAH) with connective tissue disease (CTD), APAH with repaired simple congenital systemic to pulmonary shunt (i.e., atrial septal defect, ventricular septal defect and/or patent ductus arteriosus; complete repair at least 1 year prior to Screening), APAH with human immunodeficiency virus (HIV), or APAH with portal hypertension

3. Subjects receiving at least one PAH specific therapy (ERA or PDE-5 inhibitor, or inhaled, subcutaneous, or intravenous prostacyclin or a prostacyclin analog) with the same type of therapy for at least 3 months with stable dosing 4 weeks prior to Screening. (Subjects should be receiving optimal therapy according to the disease severity)

4. Subjects using oxygen therapy by nasal cannula for at least 4 weeks prior to Screening

5. PAH diagnosis confirmed by RHC within the previous 5 years, according to the following definitions:

• PVR ≥ 400 dynes.sec.cm-5 (5 Wood units)
• mPAP ≥ 25 mmHg
• PCWP or LVEDP ≤ 15 mmHg

6. 6MWD ≥ 100 meters and ≤ 450 meters prior to randomization

7. WHO Functional Class II-IV. Subjects with WHO Functional Class IV should be treated with prostacyclin or a prostacyclin analog (subcutaneous or intravenous), plus at least one additional PAH specific therapy (ERA or PDE-5), if available to the subject and reimbursed by health insurance

8. Age between 18 and 85 years (inclusive)

9. Willingness to use INOpulse delivery device for at least 12 hours per day

10. Willingness to continue on study drug until the subject has completed Week 18 assessments

11. Female subjects of childbearing potential must have a negative pre-treatment pregnancy test (serum or urine). All female subjects should take adequate precaution to avoid pregnancy.

Exclusion Criteria

1. Subjects with known HIV infection who have a history within the past 3 months of any opportunistic pulmonary disease (e.g., tuberculosis, Pneumocystis carinii pneumonia, or other pneumonias) at the time of Screening 2. PAH associated with untreated thyroid disorders, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy 3. Subjects with pulmonary conditions that may contribute to PAH including, but not limited to, chronic bronchiectasis, cystic fibrosis, or other pulmonary condition that the Investigator may deem to contribute to the severity of the disease or impair the delivery of iNO due to airway disease 4. Subjects receiving riociguat 5. Subjects receiving oral prostanoids as monotherapy 7. PAH associated with significant venous or capillary involvement, known or suspected pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis 8. Any subject with WHO PH Groups 2, 3, 4 or 5 9. Subjects with any of the following cardiac abnormalities:

a. Underlying cardiomyopathy or clinically significant aortic or mitral valve disease in the opinion of the investigator b. Left ventricular systolic dysfunction (LVSD), i.e., left ventricular ejection fraction (LVEF) < 40% or left ventricular shortening fraction (LVSF) < 22%, as determined by local reading c. Current symptomatic coronary artery disease, myocardial infarction within 1 year, or any coronary artery interventions within 6 months 10. 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) 11. Subjects with a history of deep vein thrombosis, pulmonary embolism/infarction or prothrombotic disorder must have had chronic thromboembolic pulmonary hypertension (CTEPH) excluded by ventilation/perfusion lung (V/Q) scan 12. Severe obstructive lung disease defined as both a forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 55% of predicted value 13. 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 14. Any subject who develops or has developed a PCWP > 20 mmHg during acute vasodilator testing (AVT) 15. Systemic hypotension defined as SBP < 90 mmHg persistent at Screening after a period of rest 16. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C 17. On dialysis 18. 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 (i.e., 6MWT), including carrying and wearing the pulsed delivery device per study protocol, or medical problem(s) likely to preclude completion of the study 19. Pregnant or breastfeeding females at Screening 20. Administered L-arginine within 1 month prior to Screening 21. Known concomitant life-threatening disease with a life expectancy less than 1 year 22. Atrial septostomy within 3 months preceding randomization 23. The concurrent use of the INOpulse device with a continuous positive airway pressure (CPAP), Bilevel positive airway presure BiPAP, or any other positive pressure device.

24. Use of investigational drugs or devices within 1 month prior to Screening (other than acute vasodilator testing with iNO) 25. Any underlying medical or psychiatric condition that, in the opinion of the Investigator, makes the subject an unsuitable candidate for the study 26. Any subject who has been enrolled in any previous clinical study with inhaled NO administered through pulse delivery.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Worldwide Clinical Trials

OTHER

Sponsor Role: collaborator

Bellerophon Pulse Technologies

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ashika Ahmed, MD

Role: STUDY_DIRECTOR

Bellerophon Therapeutics

Locations

Arizona Pulmonary Specialists, Ltd

Phoenix, Arizona, United States

University of Arizona Sarver Heart Center

Tucson, Arizona, United States

Cedars-Sinai Medical Center

Beverly Hills, California, United States

UC San Diego / Pulmonary, Critical Care and Sleep Medicine Division

La Jolla, California, United States

West Los Angeles VA Healthcare Center

Los Angeles, California, United States

University of California, Davis Medical Center

Sacramento, California, United States

University of Colorado Denver

Aurora, Colorado, United States

Pulmonary Disease Specialists, PA

Kissimmee, Florida, United States

Central Florida Pulmonary Group, PA

Orlando, Florida, United States

Cleveland Clinic Florida

Weston, Florida, United States

Pulmonary and Critical Care of Atlanta

Atlanta, Georgia, United States

Piedmont Healthcare Pulmonary and Critical Care Research

Austell, Georgia, United States

Wellstar Medical Group - Pulmonary Medicine

Marietta, Georgia, United States

Bluhm Cardiovascular Institute, Clinical Trials Unit

Chicago, Illinois, United States

HeartCare Midwest

Peoria, Illinois, United States

Kentuckiana Pulmonary Associates (KPA), Inc. - Louisville

Louisville, Kentucky, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Albany Medical Center

Albany, New York, United States

New York Presbyterian Brooklyn Methodist Hospital - Division of Pulmonary/Critical Care/Sleep

Brooklyn, New York, United States

Winthrop University Hospital, Clinical Trials Center

Mineola, New York, United States

NYU Medical Center, Division Pulmonary, Critical Care and Sleep Medicine

New York, New York, United States

Montefiore Medical Center - Weiler Division

The Bronx, New York, United States

University of Cincinnati Medical Ctr, Dept of Internal Medicine / Pulmonary, Critical Care & Sleep Medicine

Cincinnati, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

The Ohio State University

Columbus, Ohio, United States

Legacy Medical Group - Pulmonary Clinic

Portland, Oregon, United States

The Oregon Clinic, PC

Portland, Oregon, United States

Temple University Hospital

Philadelphia, Pennsylvania, United States

Allegheny Singer Research Institute

Pittsburgh, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

MedTrial, LLC

Columbia, South Carolina, United States

Sioux Falls Cardiovascular

Sioux Falls, South Dakota, United States

University of Texas Southwestern Medical Center of Dallas

Dallas, Texas, United States

Pulmonary Associates of Richmond

Richmond, Virginia, United States

University of Wisconsin

Madison, Wisconsin, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

St Vincent's Public Hospital

Darlinghurst, New South Wales, Australia

Nepean Hospital

Kingswood, New South Wales, Australia

Macquarie University Hospital

Sydney, New South Wales, Australia

Concord Repatriation General Hospital

Sydney, New South Wales, Australia

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Royal Hobart Hospital

Hobart, Tasmania, Australia

Innsbruck Medical University, University Hospital for Internal Medicine VI, Pneumology

Innsbruck, Tyrol, Austria

AKH-Vienna, Medical University of Vienna

Vienna, , Austria

Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg -

Leuven, Brabant, Belgium

Hopital Erasme - Service de Cardiologie

Brussels, , Belgium

Faculty of Medicine / Peter Lougheed Center / Respiratory Research

Calgary, Alberta, Canada

Lawson Clinical Research Services / London Health Sciences Centre - VH

London, Ontario, Canada

Toronto General Hospital, University Health Network

Toronto, Ontario, Canada

Fundación Abood Shaio

Bogotá, Bogota D.C., Colombia

University Hospital centre Zagreb

Zagreb, , Croatia

Vseobecna Fakultni Nemocnice v Praze (VFN)

Prague, Bohemia, Czechia

Centre Hospitalier Universitaire (CHU) Hopitaux de Rouen - Hopital Charles Nicolle

Rouen, Normandy, France

Centre Hospitalier Universitaire de Grenoble (CHU Grenoble) - Clinique de Pneumologie

Grenoble, Rhone, France

Centre Hospitalier Universitaire de Saint Etienne

Saint-Priest-en-Jarez, Rhone, France

Hôpital Arnaud De Villeneuve - Service des Maladies Respiratoires

Montpellier, , France

CHU de Nice Hôpital Pasteur - Pavillon H - Service Pneumologie

Nice, , France

"Universitätsklinikum Freiburg - Medizinische Universitätsklinik

Freiburg im Breisgau, Baden-Wurttemberg, Germany

Thoraxklinik am Universitätsklinikum Heidelberg-Zentrum für Pulmonale Hypertension

Heidelberg, Baden-Wurttemberg, Germany

Waldburg-Zeil Kliniken - Fachkliniken Wangen Klinik für Pneumologie

Wangen, Baden-Wurttemberg, Germany

Klinikum der Universität Regensburg - Klinik und Poliklinik für Innere Medizin II

Regensburg, Bavaria, Germany

Medizinische Hochschule Hannover-Abteilung für Pneumologie

Hanover, Lower Saxony, Germany

Universitätsmedizin Greifswald Zentrum für innere Medizin Klinik und Poliklinik für Innere Medizin B

Greifswald, Mecklenburg-Vorpommern, Germany

Technische Universitaet Dresden - Universitaetsklinikum Carl Gustav Carus - Medizinische Klinik und Poliklinik I

Dresden, Saxony, Germany

Universitätsklinikum Leipzig-Dept. für Innere MedizinAbteilung für Pneumologie

Leipzig, Saxony, Germany

Helios Klinikum Erfurt

Erfurt, Thuringia, Germany

Unfallkrankenhaus Berlin-Klinik für Innere Medizin/Kardiologie

Berlin, , Germany

Barzilai University Medical Center

Ashkelon, , Israel

Soroka Medical Center

Beersheba, , Israel

Carmel Medical Center

Haifa, , Israel

The Edith Wolfson Medical Center

Holon, , Israel

Hadassah University Medical Center

Jerusalem, , Israel

Meir Medical Center - Pulmonology Dept.

Kfar Saba, , Israel

Rabin Medical Center

Petah Tikva, , Israel

Sheba Medical Center

Ramat Gan, , Israel

Azienda Ospedaliera Papa Giovanni XXIII

Bergamo, BG, Italy

Azienda Ospedaliera San Gerardo - Monza

Monza, MI, Italy

Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione

Palermo, PA, Italy

A.O.U. Policlinico Umberto I- Università La Sapienza

Roma, RM, Italy

Vrije Universiteit Medisch Centrum (VUMC)

Amsterdam, , Netherlands

Hospital Garcia de Orta

Almada, Lisbon District, Portugal

Universidade de Coimbra - Hospitais da Universidade de Coimbra (H.U.C)

Coimbra, Mondego, Portugal

Centro Hospitalar de Lisboa Norte - Hospital de Santa Maria

Lisbon, , Portugal

Clinical Center of Serbia Department of Cardiology and Polyclinic

Belgrade, , Serbia

Clinical Center of Serbia, Polyclinic, Pulomology Department

Belgrade, , Serbia

Clinical-Hospital Center Zemun

Belgrade, , Serbia

Clinical Hospital Center Bezanijska Kosa

Belgrade, , Serbia

Clinical Center of Nis, Clinic for Cardiovascular Diseases

Niš, , Serbia

Complejo Hospitalario Universitario de Santiago de Compostela

Santiago de Compostela, A Coruña, Spain

Hospital Universitario de Gran Canaria Dr. Negrin

Las Palmas de Gran Canaria, Canary Islands, Spain

Hospital Universitario Marques de Valdecilla (HUMV)

Santander, Cantabria, Spain

Hospital Virgen de la Salud (HVS)

Toledo, Castille-La Mancha, Spain

Hospital Universitario Puerta de Hierro - Madrid

Majadahonda, Madrid, Spain

Hospital Universitario Son Espases

Palma de Mallorca, Mallorca, Spain

Hospital Universitario Vall d'hebron

Barcelona, , Spain

Hospital Clinic de Barcelona

Barcelona, , Spain

Hospital Universitario de Valladolid

Valladolid, , Spain

Dnipropetrovsk Regional Clinical Center of Cardiology and Cardiac Surgery of Dnipropetrovsk Regional Council, Department of Cardiology

Dnipro, , Ukraine

Municipal Institution of health care "Kharkiv City Clinical Hospital №13", Pulmonology Department №1

Kharkiv, , Ukraine

Government Institution "L.T.Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine", Cardiopulmonology Department

Kharkiv, , Ukraine

National institute of phthisiology and pulmonology

Kyiv, , Ukraine

National Scientific Centre "M.D. STRAZHESKO INSTITUTE OF CARDIOLOGY, MAS OF UKRAINE"

Kyiv, , Ukraine

Lviv Regional Clinical Hospital, Department of Intesive Care #2

Lviv, , Ukraine

Freeman Hospital

Newcastle upon Tyne, Newcastle, United Kingdom

Golden Jubilee National Hospital

Clydebank, West Dunbartonshire, United Kingdom

Royal Free Hospital

London, , United Kingdom

Royal Brompton Hospital

London, , United Kingdom

Countries

United States; Australia; Austria; Belgium; Canada; Colombia; Croatia; Czechia; France; Germany; Israel; Italy; Netherlands; Portugal; Serbia; Spain; Ukraine; United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

PULSE-PAH-004

Identifier Type: -

Identifier Source: org_study_id