Clinical trial NCT02725372: Clinical Study of Pulsed, Inhaled Nitric Oxide Versus Placebo in Symptomatic Subjects With PAH
Official title: A Phase 3, Placebo Controlled, Double-Blind, Randomized, Clinical Study to Determine Efficacy, Safety, and Tolerability of Pulsed, Inhaled Nitric Oxide (iNO) Versus Placebo in Symptomatic Subjects With PAH (Part 1 and Part 2)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary Arterial Hypertension
PAH
Inhaled Nitric Oxide
iNO
long term oxygen therapy
oxygen therapy
Lead sponsor: Bellerophon
Sponsor class: INDUSTRY
Collaborators: name: Worldwide Clinical Trials
First posted: 2016-04-01
Enrollment: 207
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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)

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
   * Subjects who otherwise meet all the inclusion criteria and none of the exclusion criteria but have not undergone a RHC within the previous 5 years may be considered eligible for the study if they undergo a RHC and then meet the pulmonary hemodynamics criterion
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.

Primary outcomes:
measure: Change in 6-minute Walk Distance (6MWD) From Baseline (Randomization) to End of Treatment Period (Week 18)
timeFrame: Change in 6MWD from Week 2 (2 weeks after randomization and run-in period) to Week 18 (end of blinded treatment period)
Secondary outcomes:
measure: Time (in Days) to First Clinical Worsening Event (TTCW)
timeFrame: From Randomization to Week 18 (End of blinded treatment period)
measure: Number of Participants With an Improvement in World Health Organization Functional Class (WHO FC) Baseline (Randomization) to End of Treatment Period (Week 18)
timeFrame: From Randomization to Week 18 (End of blinded treatment period)
Other outcomes:
measure: Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Screening to End of Treatment Period (Week 18)
timeFrame: From Screening (28 days prior to baseline/randomization) to end of Blinded Treatment Period (Week 18)
measure: Change in Borg Dyspnea Scale Immediately Following 6-minute Walk Test (6MWT) From Baseline (Randomization) to End of Treatment Period (Week 18)
timeFrame: From Randomization to Week 18 (End of blinded treatment period)
measure: Number of Participants With an Unsatisfactory Clinical Response From Baseline (Randomization) to End of Treatment Period (Week 18)
timeFrame: From Randomization to Week 18 (End of blinded treatment period)
Locations:
city: Phoenix
country: United States
facility: Arizona Pulmonary Specialists, Ltd
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Sarver Heart Center
state: Arizona
city: Beverly Hills
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: La Jolla
country: United States
facility: UC San Diego / Pulmonary, Critical Care and Sleep Medicine Division
state: California
city: Los Angeles
country: United States
facility: West Los Angeles VA Healthcare Center
state: California
city: Sacramento
country: United States
facility: University of California, Davis Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Kissimmee
country: United States
facility: Pulmonary Disease Specialists, PA
state: Florida
city: Orlando
country: United States
facility: Central Florida Pulmonary Group, PA
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Atlanta
country: United States
facility: Pulmonary and Critical Care of Atlanta
state: Georgia
city: Austell
country: United States
facility: Piedmont Healthcare Pulmonary and Critical Care Research
state: Georgia
city: Marietta
country: United States
facility: Wellstar Medical Group - Pulmonary Medicine
state: Georgia
city: Chicago
country: United States
facility: Bluhm Cardiovascular Institute, Clinical Trials Unit
state: Illinois
city: Peoria
country: United States
facility: HeartCare Midwest
state: Illinois
city: Louisville
country: United States
facility: Kentuckiana Pulmonary Associates (KPA), Inc. - Louisville
state: Kentucky
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Albany
country: United States
facility: Albany Medical Center
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center - Weiler Division
state: New York
city: Brooklyn
country: United States
facility: New York Presbyterian Brooklyn Methodist Hospital - Division of Pulmonary/Critical Care/Sleep
state: New York
city: Mineola
country: United States
facility: Winthrop University Hospital, Clinical Trials Center
state: New York
city: New York
country: United States
facility: NYU Medical Center, Division Pulmonary, Critical Care and Sleep Medicine
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Ctr, Dept of Internal Medicine / Pulmonary, Critical Care & Sleep Medicine
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Portland
country: United States
facility: Legacy Medical Group - Pulmonary Clinic
state: Oregon
city: Portland
country: United States
facility: The Oregon Clinic, PC
state: Oregon
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny Singer Research Institute
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Columbia
country: United States
facility: MedTrial, LLC
state: South Carolina
city: Sioux Falls
country: United States
facility: Sioux Falls Cardiovascular
state: South Dakota
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center of Dallas
state: Texas
city: Richmond
country: United States
facility: Pulmonary Associates of Richmond
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Darlinghurst
country: Australia
facility: St Vincent's Public Hospital
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Macquarie University Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Innsbruck
country: Austria
facility: Innsbruck Medical University, University Hospital for Internal Medicine VI, Pneumology
state: Tirol
city: Wien
country: Austria
facility: AKH-Vienna, Medical University of Vienna
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg -
state: Brabant
city: Bruxelles
country: Belgium
facility: Hopital Erasme - Service de Cardiologie
city: Calgary
country: Canada
facility: Faculty of Medicine / Peter Lougheed Center / Respiratory Research
state: Alberta
city: London
country: Canada
facility: Lawson Clinical Research Services / London Health Sciences Centre - VH
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital, University Health Network
state: Ontario
city: Bogotá
country: Colombia
facility: Fundación Abood Shaio
state: Bogotá D.C.
city: Zagreb
country: Croatia
facility: University Hospital centre Zagreb
city: Praha 2
country: Czechia
facility: Vseobecna Fakultni Nemocnice v Praze (VFN)
state: Bohemia
city: Rouen
country: France
facility: Centre Hospitalier Universitaire (CHU) Hopitaux de Rouen - Hopital Charles Nicolle
state: Normandy
city: Grenoble
country: France
facility: Centre Hospitalier Universitaire de Grenoble (CHU Grenoble) - Clinique de Pneumologie
state: Rhone
city: St Priest en Jarez
country: France
facility: Centre Hospitalier Universitaire de Saint Etienne
state: Rhone
city: Montpellier
country: France
facility: Hôpital Arnaud De Villeneuve - Service des Maladies Respiratoires
city: Nice
country: France
facility: CHU de Nice Hôpital Pasteur - Pavillon H - Service Pneumologie
city: Freiburg
country: Germany
facility: "Universitätsklinikum Freiburg - Medizinische Universitätsklinik
state: Baden-Württemberg
city: Heidelberg
country: Germany
facility: Thoraxklinik am Universitätsklinikum Heidelberg-Zentrum für Pulmonale Hypertension
state: Baden-Württemberg
city: Wangen
country: Germany
facility: Waldburg-Zeil Kliniken - Fachkliniken Wangen Klinik für Pneumologie
state: Baden-Württemberg
city: Regensburg
country: Germany
facility: Klinikum der Universität Regensburg - Klinik und Poliklinik für Innere Medizin II
state: Bayern
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald Zentrum für innere Medizin Klinik und Poliklinik für Innere Medizin B
state: Mecklenburg-Vorpommern
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover-Abteilung für Pneumologie
state: Niedersachsen
city: Dresden
country: Germany
facility: Technische Universitaet Dresden - Universitaetsklinikum Carl Gustav Carus - Medizinische Klinik und Poliklinik I
state: Sachsen
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig-Dept. für Innere MedizinAbteilung für Pneumologie
state: Sachsen
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt
state: Thüringen
city: Berlin
country: Germany
facility: Unfallkrankenhaus Berlin-Klinik für Innere Medizin/Kardiologie
city: Ashqelon
country: Israel
facility: Barzilai University Medical Center
city: Beer Sheba
country: Israel
facility: Soroka Medical Center
city: Haifa
country: Israel
facility: Carmel Medical Center
city: Holon
country: Israel
facility: The Edith Wolfson Medical Center
city: Jerusalem
country: Israel
facility: Hadassah University Medical Center
city: Kfar Saba
country: Israel
facility: Meir Medical Center - Pulmonology Dept.
city: Petaẖ Tiqwa
country: Israel
facility: Rabin Medical Center
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
city: Bergamo
country: Italy
facility: Azienda Ospedaliera Papa Giovanni XXIII
state: BG
city: Monza
country: Italy
facility: Azienda Ospedaliera San Gerardo - Monza
state: MI
city: Palermo
country: Italy
facility: Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione
state: PA
city: Roma
country: Italy
facility: A.O.U. Policlinico Umberto I- Università La Sapienza
state: RM
city: Amsterdam
country: Netherlands
facility: Vrije Universiteit Medisch Centrum (VUMC)
city: Almada
country: Portugal
facility: Hospital Garcia de Orta
state: Lisbon
city: Coimbra
country: Portugal
facility: Universidade de Coimbra - Hospitais da Universidade de Coimbra (H.U.C)
state: Mondego
city: Lisbon
country: Portugal
facility: Centro Hospitalar de Lisboa Norte - Hospital de Santa Maria
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia Department of Cardiology and Polyclinic
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia, Polyclinic, Pulomology Department
city: Belgrade
country: Serbia
facility: Clinical-Hospital Center Zemun
city: Belgrade
country: Serbia
facility: Clinical Hospital Center Bezanijska Kosa
city: Nis
country: Serbia
facility: Clinical Center of Nis, Clinic for Cardiovascular Diseases
city: Santiago de Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago de Compostela
state: A Coruña
city: Las Palmas de Gran Canaria
country: Spain
facility: Hospital Universitario de Gran Canaria Dr. Negrin
state: Canarias
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla (HUMV)
state: Cantabria
city: Toledo
country: Spain
facility: Hospital Virgen de la Salud (HVS)
state: Castile - La Mancha
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro - Madrid
state: Madrid
city: Palma de Mallorca
country: Spain
facility: Hospital Universitario Son Espases
state: Mallorca
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Valladolid
country: Spain
facility: Hospital Universitario de Valladolid
city: Dnepropetrovsk
country: Ukraine
facility: Dnipropetrovsk Regional Clinical Center of Cardiology and Cardiac Surgery of Dnipropetrovsk Regional Council, Department of Cardiology
city: Kharkiv
country: Ukraine
facility: Municipal Institution of health care "Kharkiv City Clinical Hospital №13", Pulmonology Department №1
city: Kharkiv
country: Ukraine
facility: Government Institution "L.T.Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine", Cardiopulmonology Department
city: Kyiv
country: Ukraine
facility: National institute of phthisiology and pulmonology
city: Kyiv
country: Ukraine
facility: National Scientific Centre "M.D. STRAZHESKO INSTITUTE OF CARDIOLOGY, MAS OF UKRAINE"
city: Lviv
country: Ukraine
facility: Lviv Regional Clinical Hospital, Department of Intesive Care #2
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital
state: Newcastle
city: Clydebank
country: United Kingdom
facility: Golden Jubilee National Hospital
state: West Dunbartonshire
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: Royal Brompton Hospital
Study officials:
affiliation: Bellerophon Therapeutics
name: Ashika Ahmed, MD
role: STUDY_DIRECTOR
References: