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

NCT02725372 | Terminated Phase 3 Results DMC

• 1 other identifier: PULSE-PAH-004
• Study Type: interventional
• Target: 207
• Locations: 17 countries
• Sites: 102

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

Conditions

Pulmonary Arterial Hypertension

Keywords

Pulmonary Arterial Hypertension; PAH; Inhaled Nitric Oxide; iNO; long term oxygen therapy; oxygen therapy

Outcome Measures

Primary Outcomes (1)

• Change in 6-minute Walk Distance (6MWD) From Baseline (Randomization) to End of Treatment Period (Week 18)

  The 6-minute walk distance test (6MWD) is a non-encouraged test performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. All patients were required to complete two walks while on chronic oxygen therapy given at a standard rate during the test and throughout the study while using the investigational product (INOpulse device with nitric oxide or matching placebo). The average of two walks at Week 2 visit (2 weeks after Run-In) was used as the Baseline 6MWD.

  Change in 6MWD from Week 2 (2 weeks after randomization and run-in period) to Week 18 (end of blinded treatment period)

Secondary Outcomes (2)

• Time (in Days) to First Clinical Worsening Event (TTCW)

  From Randomization to Week 18 (End of blinded treatment period)

• Number of Participants With an Improvement in World Health Organization Functional Class (WHO FC) Baseline (Randomization) to End of Treatment Period (Week 18)

  From Randomization to Week 18 (End of blinded treatment period)

Other Outcomes (3)

• Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Screening to End of Treatment Period (Week 18)

  From Screening (28 days prior to baseline/randomization) to end of Blinded Treatment Period (Week 18)

• Change in Borg Dyspnea Scale Immediately Following 6-minute Walk Test (6MWT) From Baseline (Randomization) to End of Treatment Period (Week 18)

  From Randomization to Week 18 (End of blinded treatment period)

• Number of Participants With an Unsatisfactory Clinical Response From Baseline (Randomization) to End of Treatment Period (Week 18)

  From Randomization to Week 18 (End of blinded treatment period)

Study Arms (2)

Inhaled Nitric Oxide 75mcg/KgIBW/Hr

EXPERIMENTAL

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)

Drug: Inhaled Nitric Oxide 75 mcg/kg IBW/hr

Placebo

PLACEBO COMPARATOR

Part 1: Placebo dose setting 15mcg/kg IBW/hr Run In Period / Placebo dose setting 75 mcg/kg IBW/hr treatment period

Drug: Placebo

Interventions

Inhaled Nitric Oxide 75 mcg/kg IBW/hr 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)

Also known as: Inhaled Nitric Oxide, iNO

Inhaled Nitric Oxide 75mcg/KgIBW/Hr

Placebo 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

Also known as: Inhaled Nitric Oxide, iNO

Placebo

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed Informed Consent Form (and assent as appropriate) prior to the initiation of any study mandated procedures or assessments
• 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
• 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)
• Subjects using oxygen therapy by nasal cannula for at least 4 weeks prior to Screening
• 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

You may not qualify if:

• MWD ≥ 100 meters and ≤ 450 meters prior to randomization
• 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
• Age between 18 and 85 years (inclusive)
• Willingness to use INOpulse delivery device for at least 12 hours per day
• Willingness to continue on study drug until the subject has completed Week 18 assessments
• 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.
• \. 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.
• \. 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.

Sponsors & Collaborators

• Bellerophon Pulse Technologies: lead
• Worldwide Clinical Trials: collaborator

Study Sites (109)

Arizona Pulmonary Specialists, Ltd

Phoenix, Arizona, 85012, United States

Location

University of Arizona Sarver Heart Center

Tucson, Arizona, 85724-5046, United States

Location

Cedars-Sinai Medical Center

Beverly Hills, California, 90211, United States

Location

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

La Jolla, California, 92093, United States

Location

West Los Angeles VA Healthcare Center

Los Angeles, California, 90073, United States

Location

University of California, Davis Medical Center

Sacramento, California, 95817, United States

Location

University of Colorado Denver

Aurora, Colorado, 80045, United States

Location

Pulmonary Disease Specialists, PA

Kissimmee, Florida, 34741, United States

Location

Central Florida Pulmonary Group, PA

Orlando, Florida, 32803-5727, United States

Location

Cleveland Clinic Florida

Weston, Florida, 33331, United States

Location

Pulmonary and Critical Care of Atlanta

Atlanta, Georgia, 30342, United States

Location

Piedmont Healthcare Pulmonary and Critical Care Research

Austell, Georgia, 30106, United States

Location

Wellstar Medical Group - Pulmonary Medicine

Marietta, Georgia, 30060, United States

Location

Bluhm Cardiovascular Institute, Clinical Trials Unit

Chicago, Illinois, 60611, United States

Location

HeartCare Midwest

Peoria, Illinois, 61616, United States

Location

Kentuckiana Pulmonary Associates (KPA), Inc. - Louisville

Louisville, Kentucky, 40202-1332, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Nebraska Medical Center

Omaha, Nebraska, 68198-5590, United States

Location

Albany Medical Center

Albany, New York, 12208, United States

Location

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

Brooklyn, New York, 11215, United States

Location

Winthrop University Hospital, Clinical Trials Center

Mineola, New York, 11501, United States

Location

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

New York, New York, 10279, United States

Location

Montefiore Medical Center - Weiler Division

The Bronx, New York, 10461, United States

Location

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

Cincinnati, Ohio, 45267-0564, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

The Ohio State University

Columbus, Ohio, 43065, United States

Location

Legacy Medical Group - Pulmonary Clinic

Portland, Oregon, 97210, United States

Location

The Oregon Clinic, PC

Portland, Oregon, 97220, United States

Location

Temple University Hospital

Philadelphia, Pennsylvania, 19140, United States

Location

Allegheny Singer Research Institute

Pittsburgh, Pennsylvania, 15212, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

MedTrial, LLC

Columbia, South Carolina, 29204, United States

Location

Sioux Falls Cardiovascular

Sioux Falls, South Dakota, 57108, United States

Location

University of Texas Southwestern Medical Center of Dallas

Dallas, Texas, 75390-8550, United States

Location

Pulmonary Associates of Richmond

Richmond, Virginia, 23229, United States

Location

University of Wisconsin

Madison, Wisconsin, 53792-1615, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

St Vincent's Public Hospital

Darlinghurst, New South Wales, 2010, Australia

Location

Nepean Hospital

Kingswood, New South Wales, 2747, Australia

Location

Macquarie University Hospital

Sydney, New South Wales, 2109, Australia

Location

Concord Repatriation General Hospital

Sydney, New South Wales, 2139, Australia

Location

Princess Alexandra Hospital

Woolloongabba, Queensland, 4102, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

Royal Hobart Hospital

Hobart, Tasmania, 7000, Australia

Location

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

Innsbruck, Tyrol, 6020, Austria

Location

AKH-Vienna, Medical University of Vienna

Vienna, 1090, Austria

Location

Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg -

Leuven, Brabant, 3000, Belgium

Location

Hopital Erasme - Service de Cardiologie

Brussels, 1070, Belgium

Location

Faculty of Medicine / Peter Lougheed Center / Respiratory Research

Calgary, Alberta, T1Y 6J4, Canada

Location

Lawson Clinical Research Services / London Health Sciences Centre - VH

London, Ontario, N6A 5W9, Canada

Location

Toronto General Hospital, University Health Network

Toronto, Ontario, M5G 2C4, Canada

Location

Fundación Abood Shaio

Bogotá, Bogota D.C., Colombia

Location

University Hospital centre Zagreb

Zagreb, 10000, Croatia

Location

Vseobecna Fakultni Nemocnice v Praze (VFN)

Prague, Bohemia, 128 02, Czechia

Location

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

Rouen, Normandy, 76031, France

Location

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

Grenoble, Rhone, 38043, France

Location

Centre Hospitalier Universitaire de Saint Etienne

Saint-Priest-en-Jarez, Rhone, 42270, France

Location

Hôpital Arnaud De Villeneuve - Service des Maladies Respiratoires

Montpellier, 34295, France

Location

CHU de Nice Hôpital Pasteur - Pavillon H - Service Pneumologie

Nice, 06001, France

Location

"Universitätsklinikum Freiburg - Medizinische Universitätsklinik

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

Thoraxklinik am Universitätsklinikum Heidelberg-Zentrum für Pulmonale Hypertension

Heidelberg, Baden-Wurttemberg, 69126, Germany

Location

Waldburg-Zeil Kliniken - Fachkliniken Wangen Klinik für Pneumologie

Wangen, Baden-Wurttemberg, 88239, Germany

Location

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

Regensburg, Bavaria, 93053, Germany

Location

Medizinische Hochschule Hannover-Abteilung für Pneumologie

Hanover, Lower Saxony, 30625, Germany

Location

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

Greifswald, Mecklenburg-Vorpommern, 17475, Germany

Location

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

Dresden, Saxony, 01307, Germany

Location

Universitätsklinikum Leipzig-Dept. für Innere MedizinAbteilung für Pneumologie

Leipzig, Saxony, 04103, Germany

Location

Helios Klinikum Erfurt

Erfurt, Thuringia, 99089, Germany

Location

Unfallkrankenhaus Berlin-Klinik für Innere Medizin/Kardiologie

Berlin, 12683, Germany

Location

Barzilai University Medical Center

Ashkelon, 7830604, Israel

Location

Soroka Medical Center

Beersheba, 84101, Israel

Location

Carmel Medical Center

Haifa, 3436212, Israel

Location

The Edith Wolfson Medical Center

Holon, 58100, Israel

Location

Hadassah University Medical Center

Jerusalem, Israel

Location

Meir Medical Center - Pulmonology Dept.

Kfar Saba, 4428164, Israel

Location

Rabin Medical Center

Petah Tikva, 49100, Israel

Location

Sheba Medical Center

Ramat Gan, 5265601, Israel

Location

Azienda Ospedaliera Papa Giovanni XXIII

Bergamo, BG, 24129, Italy

Location

Azienda Ospedaliera San Gerardo - Monza

Monza, MI, 20900, Italy

Location

Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione

Palermo, PA, 90127, Italy

Location

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

Roma, RM, 00161, Italy

Location

Vrije Universiteit Medisch Centrum (VUMC)

Amsterdam, 1081 HV, Netherlands

Location

Hospital Garcia de Orta

Almada, Lisbon District, 2801-951, Portugal

Location

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

Coimbra, Mondego, 3049, Portugal

Location

Centro Hospitalar de Lisboa Norte - Hospital de Santa Maria

Lisbon, 1649-035, Portugal

Location

Clinical Center of Serbia Department of Cardiology and Polyclinic

Belgrade, 11000, Serbia

Location

Clinical Center of Serbia, Polyclinic, Pulomology Department

Belgrade, 11000, Serbia

Location

Clinical-Hospital Center Zemun

Belgrade, 11070, Serbia

Location

Clinical Hospital Center Bezanijska Kosa

Belgrade, 11080, Serbia

Location

Clinical Center of Nis, Clinic for Cardiovascular Diseases

Niš, 18000, Serbia

Location

Complejo Hospitalario Universitario de Santiago de Compostela

Santiago de Compostela, A Coruña, 15706, Spain

Location

Hospital Universitario de Gran Canaria Dr. Negrin

Las Palmas de Gran Canaria, Canary Islands, 35020, Spain

Location

Hospital Universitario Marques de Valdecilla (HUMV)

Santander, Cantabria, 39008, Spain

Location

Hospital Virgen de la Salud (HVS)

Toledo, Castille-La Mancha, 45004, Spain

Location

Hospital Universitario Puerta de Hierro - Madrid

Majadahonda, Madrid, 28222, Spain

Location

Hospital Universitario Son Espases

Palma de Mallorca, Mallorca, 7120, Spain

Location

Hospital Universitario Vall d'hebron

Barcelona, 8035, Spain

Location

Hospital Clinic de Barcelona

Barcelona, 8036, Spain

Location

Hospital Universitario de Valladolid

Valladolid, 47003, Spain

Location

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

Dnipro, 49094, Ukraine

Location

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

Kharkiv, 61035, Ukraine

Location

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

Kharkiv, 61039, Ukraine

Location

National institute of phthisiology and pulmonology

Kyiv, 03680, Ukraine

Location

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

Kyiv, 03680, Ukraine

Location

Lviv Regional Clinical Hospital, Department of Intesive Care #2

Lviv, 79010, Ukraine

Location

Freeman Hospital

Newcastle upon Tyne, Newcastle, NE7 7DN, United Kingdom

Location

Golden Jubilee National Hospital

Clydebank, West Dunbartonshire, G81 4DY, United Kingdom

Location

Royal Free Hospital

London, NW3 3QG, United Kingdom

Location

Royal Brompton Hospital

London, SW3 6NP, United Kingdom

Location

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Limitations and Caveats

Planned Interim Analysis resulted in early termination due to futility, leading to small numbers of study participants analyzed. Analysis is based on Part 1 Blinded Treatment Period (up to 18 Weeks) only.

Results Point of Contact

• Title: Bobae Kim
• Organization: Bellerophon Therapeutics Inc

bobae.kim@bellerophon.com

(917) 675-2254

Study Officials

• Ashika Ahmed, MD

  Bellerophon Therapeutics

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 19, 2016
• First Posted: April 1, 2016
• Study Start: April 1, 2016
• Primary Completion: August 1, 2018
• Study Completion: August 1, 2018
• Last Updated: February 21, 2023
• Results First Posted: January 25, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (5); AU (2); CA (3); CZ (1); CO (1); DE (10); ES (9); UA (6); GB (4); IL (8); US (37); IT (4); BE (2); NL (1); SE (5); PT (3); CR (1)