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

Pulmonary Arterial Hypertension Clinical Trial

— INOvation-1  

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02725372
• Other study ID #: PULSE-PAH-004
• Status: Terminated
• Phase: Phase 3
• Start date: April 2016
• Est. completion date: August 2018

Study information

• Verified date: January 2023
• Source: Bellerophon
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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)

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 207
• Est. completion date: August 2018
• Est. primary completion date: August 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• 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)
• 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

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	St Vincent's Public Hospital	Darlinghurst	New South Wales
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Nepean Hospital	Kingswood	New South Wales
Australia	Concord Repatriation General Hospital	Sydney	New South Wales
Australia	Macquarie University Hospital	Sydney	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Austria	Innsbruck Medical University, University Hospital for Internal Medicine VI, Pneumology	Innsbruck	Tirol
Austria	AKH-Vienna, Medical University of Vienna	Wien
Belgium	Hopital Erasme - Service de Cardiologie	Bruxelles
Belgium	Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg -	Leuven	Brabant
Canada	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
Colombia	Fundación Abood Shaio	Bogotá	Bogotá D.C.
Croatia	University Hospital centre Zagreb	Zagreb
Czechia	Vseobecna Fakultni Nemocnice v Praze (VFN)	Praha 2	Bohemia
France	Centre Hospitalier Universitaire de Grenoble (CHU Grenoble) - Clinique de Pneumologie	Grenoble	Rhone
France	Hôpital Arnaud De Villeneuve - Service des Maladies Respiratoires	Montpellier
France	CHU de Nice Hôpital Pasteur - Pavillon H - Service Pneumologie	Nice
France	Centre Hospitalier Universitaire (CHU) Hopitaux de Rouen - Hopital Charles Nicolle	Rouen	Normandy
France	Centre Hospitalier Universitaire de Saint Etienne	St Priest en Jarez	Rhone
Germany	Unfallkrankenhaus Berlin-Klinik für Innere Medizin/Kardiologie	Berlin
Germany	Technische Universitaet Dresden - Universitaetsklinikum Carl Gustav Carus - Medizinische Klinik und Poliklinik I	Dresden	Sachsen
Germany	Helios Klinikum Erfurt	Erfurt	Thüringen
Germany	"Universitätsklinikum Freiburg - Medizinische Universitätsklinik	Freiburg	Baden-Württemberg
Germany	Universitätsmedizin Greifswald Zentrum für innere Medizin Klinik und Poliklinik für Innere Medizin B	Greifswald	Mecklenburg-Vorpommern
Germany	Medizinische Hochschule Hannover-Abteilung für Pneumologie	Hannover	Niedersachsen
Germany	Thoraxklinik am Universitätsklinikum Heidelberg-Zentrum für Pulmonale Hypertension	Heidelberg	Baden-Württemberg
Germany	Universitätsklinikum Leipzig-Dept. für Innere MedizinAbteilung für Pneumologie	Leipzig	Sachsen
Germany	Klinikum der Universität Regensburg - Klinik und Poliklinik für Innere Medizin II	Regensburg	Bayern
Germany	Waldburg-Zeil Kliniken - Fachkliniken Wangen Klinik für Pneumologie	Wangen	Baden-Württemberg
Israel	Barzilai University Medical Center	Ashqelon
Israel	Soroka Medical Center	Beer Sheba
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	Peta? Tiqwa
Israel	Sheba Medical Center	Ramat Gan
Italy	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
Netherlands	Vrije Universiteit Medisch Centrum (VUMC)	Amsterdam
Portugal	Hospital Garcia de Orta	Almada	Lisbon
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
Serbia	Clinical Center of Serbia Department of Cardiology and Polyclinic	Belgrade
Serbia	Clinical Center of Serbia, Polyclinic, Pulomology Department	Belgrade
Serbia	Clinical Hospital Center Bezanijska Kosa	Belgrade
Serbia	Clinical-Hospital Center Zemun	Belgrade
Serbia	Clinical Center of Nis, Clinic for Cardiovascular Diseases	Nis
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario Vall d'hebron	Barcelona
Spain	Hospital Universitario de Gran Canaria Dr. Negrin	Las Palmas de Gran Canaria	Canarias
Spain	Hospital Universitario Puerta de Hierro - Madrid	Majadahonda	Madrid
Spain	Hospital Universitario Son Espases	Palma de Mallorca	Mallorca
Spain	Hospital Universitario Marques de Valdecilla (HUMV)	Santander	Cantabria
Spain	Complejo Hospitalario Universitario de Santiago de Compostela	Santiago de Compostela	A Coruña
Spain	Hospital Virgen de la Salud (HVS)	Toledo	Castile - La Mancha
Spain	Hospital Universitario de Valladolid	Valladolid
Ukraine	Dnipropetrovsk Regional Clinical Center of Cardiology and Cardiac Surgery of Dnipropetrovsk Regional Council, Department of Cardiology	Dnepropetrovsk
Ukraine	Government Institution "L.T.Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine", Cardiopulmonology Department	Kharkiv
Ukraine	Municipal Institution of health care "Kharkiv City Clinical Hospital ?13", Pulmonology Department ?1	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
United Kingdom	Golden Jubilee National Hospital	Clydebank	West Dunbartonshire
United Kingdom	Royal Brompton Hospital	London
United Kingdom	Royal Free Hospital	London
United Kingdom	Freeman Hospital	Newcastle Upon Tyne	Newcastle
United States	Albany Medical Center	Albany	New York
United States	Pulmonary and Critical Care of Atlanta	Atlanta	Georgia
United States	University of Colorado Denver	Aurora	Colorado
United States	Piedmont Healthcare Pulmonary and Critical Care Research	Austell	Georgia
United States	Cedars-Sinai Medical Center	Beverly Hills	California
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Montefiore Medical Center - Weiler Division	Bronx	New York
United States	New York Presbyterian Brooklyn Methodist Hospital - Division of Pulmonary/Critical Care/Sleep	Brooklyn	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Bluhm Cardiovascular Institute, Clinical Trials Unit	Chicago	Illinois
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	MedTrial, LLC	Columbia	South Carolina
United States	The Ohio State University	Columbus	Ohio
United States	University of Texas Southwestern Medical Center of Dallas	Dallas	Texas
United States	Pulmonary Disease Specialists, PA	Kissimmee	Florida
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	Kentuckiana Pulmonary Associates (KPA), Inc. - Louisville	Louisville	Kentucky
United States	University of Wisconsin	Madison	Wisconsin
United States	Wellstar Medical Group - Pulmonary Medicine	Marietta	Georgia
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
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	University of Nebraska Medical Center	Omaha	Nebraska
United States	Central Florida Pulmonary Group, PA	Orlando	Florida
United States	HeartCare Midwest	Peoria	Illinois
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Arizona Pulmonary Specialists, Ltd	Phoenix	Arizona
United States	Allegheny Singer Research Institute	Pittsburgh	Pennsylvania
United States	Legacy Medical Group - Pulmonary Clinic	Portland	Oregon
United States	The Oregon Clinic, PC	Portland	Oregon
United States	Pulmonary Associates of Richmond	Richmond	Virginia
United States	University of California, Davis Medical Center	Sacramento	California
United States	Sioux Falls Cardiovascular	Sioux Falls	South Dakota
United States	University of Arizona Sarver Heart Center	Tucson	Arizona
United States	Cleveland Clinic Florida	Weston	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Bellerophon Pulse Technologies	Worldwide Clinical Trials

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Screening to End of Treatment Period (Week 18)	Plasma NT-proBNP concentration is a useful biomarker for the severity of PAH as it is associated with changes in right heart morphology and function. NT-proBNP sample collection occurred at Screening visit (prior to starting study drug at Randomization) and after 16 weeks of blinded treatment therapy (Week 18). The change in NT-proBNP between Screening (28 days prior to baseline/randomization) and the end of blinded treatment period (Week 18) is reported.	From Screening (28 days prior to baseline/randomization) to end of Blinded Treatment Period (Week 18)
Other	Change in Borg Dyspnea Scale Immediately Following 6-minute Walk Test (6MWT) From Baseline (Randomization) to End of Treatment Period (Week 18)	The Borg dyspneas score is a self-rating scale to evaluate the severity of dyspnea (from 0 "no shortness of breath at all" to 10 "very, very severe / maximal") shortness of breath, where high score on the scale signifies a worse score. The self assessment was collected from each participant immediately after each 6-minute walk test throughout the blinded treatment period. The change in Borg dyspnea Score at the end of the blinded treatment period (Week 18) compared to baseline (randomization) (Week 0) is reported.	From Randomization to Week 18 (End of blinded treatment period)
Other	Number of Participants With an Unsatisfactory Clinical Response From Baseline (Randomization) to End of Treatment Period (Week 18)	Unsatisfactory Clinical Response was defined as the number of participants with WHO Functional Class III (defined as moderate dyspnea with routine activities and activities of daily living. No symptoms at rest.) or Class IV (defined as inability to perform even minimal activities. Signs and symptoms of right heart failure may be present. Dyspnea present at rest) with no improvement in 6-minute walk distance (6MWD) from baseline to end of blinded treatment period (Week 18).	From Randomization to Week 18 (End of blinded treatment period)
Primary	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	Time (in Days) to First Clinical Worsening Event (TTCW)	Clinical worsening was assessed continuously from Randomization to Week 18 (End of blinded treatment period). Clinical worsening events were defined as death (all causes), atrial septostomy, hospitalization due to worsening of pulmonary arterial hypertension (PAH), initiation of new pulmonary arterial hypertension treatment including endothelin receptor antagonists [ERAs], phosphodiesterase type-5 [PDE-5] inhibitors or prostanoids, an increase in existing treatment of ERA or PDE-5, increase in the dose or frequency of an inhaled prostanoids, or an increase in the dose of an intravenous or subcutaneous prostanoids by >10%, a decrease of >15% from baseline or >30% compared with the last study related measurement in 6MWD or worsening of WHO Functional Class (e.g., from Class II to Class III or IV, OR Class III to Class IV). All worsening events were entered by the study sites into the eCRF.	From Randomization to Week 18 (End of blinded treatment period)
Secondary	Number of Participants With an Improvement in World Health Organization Functional Class (WHO FC) Baseline (Randomization) to End of Treatment Period (Week 18)	WHO FC (where Class I is defined as "No limitations in daily physical activities. No symptoms of dyspnea and with routine exertion" and Class IV is defined as "Inability to perform even minimal activities. Signs and symptoms of right heart failure may be present. Dyspnea present at rest") for PAH was taken at randomization (Week 0) for all participants and was assessed after blinded treatment (Week 18). The number of participants that had an improvement (lower functional class) as compared to baseline were measured.	From Randomization to Week 18 (End of blinded treatment period)