Efficacy and Safety of Seralutinib in Adult Subjects With PAH (PROSERA)

Phase 3

Recruiting

• Conditions: Pulmonary Arterial Hypertension
• Interventions: Drug: Placebo; Drug: Seralutinib; Device: Generic Dry Powder Inhaler

• Registration Number: NCT05934526
• Lead Sponsor: GB002, Inc.

Brief Summary

The primary objective of the study is to determine the effect of seralutinib on improving exercise capacity in subjects with WHO Group 1 PAH who are FC II or III. The secondary objective for this trial is to determine time to clinical worsening.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-06-28
• Study First Submitted QC: 2023-06-28
• Study First Posted: 2023-07-07
• Study Start: 2023-12-28
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-23
• Last Update Posted: 2024-12-27
• Primary Completion: 2025-09
• Study Completion: 2025-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 350

Inclusion Criteria

1. Adult subjects aged 18 to 75 years.

2. Body mass index (BMI) ≥ 15 kg/m^2 and ≤ 40 kg/m^2.

3. Diagnosis of PAH classified by one of the following:

   1. Idiopathic PAH (IPAH) or heritable PAH (HPAH).
   2. PAH associated with connective tissue disease (CTD-APAH); PAH associated with anorexigen or PAH associated with methamphetamine use.
   3. Congenital heart disease with simple systemic to pulmonary shunt at least 1 year after surgical repair.

4. 6MWDs ≥ 150 meters and ≤ 475 meters during Screening prior to randomization.

5. WHO FC II or III.

6. US Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) Lite 2 Risk Score ≥ 5 OR NT-proBNP ≥ 300 ng/L OR PVR ≥ 800 dyne s/cm^5.

7. Cardiac catheterization within the screening period, or a standard of care right heart catheterization (RHC) (with pressure wave forms available for review) up to 48 weeks prior to Screening.

   1. Mean pulmonary arterial pressure (mPAP) > 20 mmHg (at rest), AND
   2. Pulmonary vascular resistance (PVR) ≥ 400 dyne·s/cm^5, AND
   3. Pulmonary capillary wedge pressure (PCWP) or left ventricle end-diastolic pressure (LVEDP) ≤ 15 mmHg.

8. Treatment with at least one allowed background PAH disease-specific medication prior to Screening.

   1. Subjects receiving treatment with endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, guanylate cyclase stimulators, and/or prostacyclin analogues or prostacyclin receptor agonists are eligible only if on a stable dose for at least 12 weeks prior to and throughout Screening.
   2. Subjects receiving treatment with sotatercept are eligible only if on a stable dose of sotatercept for at least 24 weeks prior to and throughout Screening, with a RHC performed during Screening (or within 2 weeks prior to Screening).

9. Pulmonary function tests (PFTs) at Screening or completed no more than 12 weeks prior to Screening.

10. Women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening and on Day 1 before first administration of Investigational Product (IP).

11. WOCBP who are not abstinent and intend to be sexually active with a non-sterilized male partner must be willing to use a highly effective method of contraception from consent through 30 days following the last administration of IP.

12. Male subjects: Non-sterilized male subjects who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom from consent through 90 days after the last dose of IP.

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Exclusion Criteria

1. Evidence of chronic thromboembolic disease or acute pulmonary embolism.

2. Uncontrolled systemic hypertension as evidenced by systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg.

3. Systolic blood pressure < 90 mm Hg during Screening.

4. WHO Pulmonary Hypertension Group 2 - 5.

5. Human immunodeficiency virus (HIV)-associated PAH, schistosomiasis associated PAH, PAH associated with portal hypertension, or pulmonary veno-occlusive disease (PVOD).

6. Recent history of left-sided heart disease and/or clinically significant cardiac disease within 48 weeks of Screening.

7. Left ventricular ejection fraction (LVEF) ≤ 50% within 24 weeks of Screening.

8. Hemodynamically significant valvular heart disease or uncontrolled symptomatic coronary disease.

9. History of atrial septostomy.

10. Uncontrolled atrial fibrillation or paroxysmal atrial fibrillation.

11. Untreated severe obstructive sleep apnea.

12. Hepatic dysfunction defined as Child-Pugh Class A or higher, or as evidenced by one of the following at Screening: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 x upper limit of normal (ULN) or total bilirubin ≥ 1.5 x ULN.

13. Severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or IP administration (eg, history of intracranial hemorrhage, recurrent syncope).

14. Any musculoskeletal disease, injury, or any other disease that limits evaluation of 6MWT.

15. Initiation of an exercise program for cardiopulmonary rehabilitation within 12 weeks prior to Screening or planned during the study.

16. Pregnant or nursing or intends to become pregnant during the duration of the study.

17. Body weight < 37 kg at Screening.

18. Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m^2 Hemoglobin (Hgb) concentration < 8.5 g/dL at Screening.

19. Evidence of active or latent Human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C, or tuberculosis (TB) infection at Screening.

20. Prior/concurrent treatment with tyrosine kinase inhibitors or activin signaling inhibitors:

    1. Tyrosine kinase inhibitors, other than Janus kinase inhibitors approved for systemic autoimmune rheumatic diseases, within 12 weeks prior to Screening.
    2. Activin signaling inhibitors within 5 half-lives prior to Screening.

21. Requirement of IV inotropes (ie, levosimendan, dopamine, dobutamine, milrinone, norepinephrine) or IV diuretics for more than 24 hours within 4 weeks prior to Screening.

22. Subjects currently receiving oral anticoagulants (ie, warfarin/other vitamin K antagonists or direct-acting oral anticoagulants [DOACs]) if any of the following criteria are met:

    a. History within 24 weeks of Screening of: i. Syncope, or ii. Symptomatic bleeding in a critical area or organ iii. Intramuscular with compartment syndrome, or iv. Bleeding causing a fall in hemoglobin levels of 1.24 mmol/L (20 g/L or greater) or more, or v. Bleeding leading to a transfusion of 2 U or more of whole blood or red blood cells.

    b. History of central nervous system pathology.

    c. History of clinically significant (massive) hemoptysis.

    d. If on warfarin/other vitamin K antagonist, uncontrolled International normalized ratio (eg, INR > 3) as assessed.

    e. Platelet count < 150 x 10^9/L at Screening.

    f. Concomitant use of antiplatelet agents.

    g. CTD-APAH

    h. Concomitant use of sotatercept.

23. Prior participation in seralutinib studies and/or prior treatment with seralutinib.

24. Currently participating in or has participated in a study of an investigational agent or has used an investigational device for the treatment of PAH within 12 weeks or 5 half-lives of the investigational agent, whichever is longer, prior to Screening.

25. Current use of inhaled tobacco- or nicotine-containing products (including e-vapor products) and/or inhaled marijuana.

26. Current alcohol use disorder based on the opinion of the Investigator, and/or a positive test for drugs of abuse.

27. Subjects with a history of severe milk protein allergy or known intolerance to lactose.

28. QT interval corrected for heart rate using Fridericia's formula (QTcF) of > 500 msec.

29. Have any other condition or reason that, in the opinion of the Investigator or in the opinion of the Sponsor's Medical Monitor (MM) (or designee) in consultation with the Investigator, would prohibit the subject from participating in the study.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Generic Dry Powder Inhaler	Placebo inhaled orally twice daily (BID) up to 48 weeks
Seralutinib 90 mg	Generic Dry Powder Inhaler	Seralutinib inhaled orally BID up to 48 weeks
Placebo	Placebo	Placebo inhaled orally twice daily (BID) up to 48 weeks
Seralutinib 90 mg	Seralutinib	Seralutinib inhaled orally BID up to 48 weeks

Primary Outcome Measures

Name	Time	Method
Change in distance achieved on the six-minute walk test (6MWT), six-minute walk distance (Δ6MWD) from baseline to Week 24	Baseline to 24 weeks

Secondary Outcome Measures

Name	Time	Method
Change in NT-proBNP from baseline to Week 24	Baseline to 24 weeks
Proportion of subjects with each of the Clinical Worsening Outcomes:	Baseline to 52 weeks	1. Death (all causes); 2. Hospitalization for signs and symptoms of worsening PAH (≥ 24 hours); 3. Worsening-related listing for or receipt of lung and/or heart/lung transplantation; 4. Atrial septostomy performed; 5. Worsening PAH requiring initiation of therapy with an additional approved background PAH disease-specific medication or the need to increase the dose of parenteral (IV or subcutaneous infusion) prostacyclin by 10% or more; 6. Disease progression, defined by both of the following events occurring at any time, even if they began at different times, as compared to their baseline values: 1. Decrease in 6MWD of ≥ 15% on two consecutive tests, performed a minimum of 4 hours but no more than 1 week apart AND; 2. Worsened WHO FC
Time to first event of Clinical Worsening from first dose of Investigational Product (IP) through end of study	Baseline to 48 weeks
Proportion of subjects who improve from baseline in WHO FC or maintain WHO FC II	Baseline to 24 weeks
Change in PAH-SYMPACT™ from baseline to Week 24	Baseline to 24 weeks
Incidence of treatment-emergent adverse events (TEAEs), serious TEAEs (SAEs), and treatment-emergent adverse events of special interest (AESIs)	Baseline to 52 weeks
Proportion of subjects who achieve all of the following components of clinical improvement at Week 24, in the absence of clinical worsening:	Baseline to 24 weeks	1. Improvement from baseline in World Health Organization (WHO) functional class (FC) or maintenance of WHO FC II; 2. Decrease from baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP) of ≥ 30% or decrease and maintenance at \< 300 ng/L; 3. Increase from baseline in 6MWD of ≥ 10% or ≥ 30 m
Proportion of subjects with ≥ 1 point decrease from baseline in US Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) Lite 2 Risk Score at Week 24	Baseline to 24 weeks
Change in Euro-QoL - 5 Dimensions - 5 Levels (EQ-5D-5L) from baseline to Week 24	Baseline to 24 weeks

Trial Locations

Locations (185)

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

Valley Advanced Lung Diseases Institute; 🇺🇸 Fresno, California, United States

Keck Medical Center of USC; 🇺🇸 Los Angeles, California, United States

Dept of Veterans Affairs Greater Los Angeles Healthcare System; 🇺🇸 Los Angeles, California, United States

University of California, Irvine Medical Center; 🇺🇸 Orange, California, United States

UC Davis Health; 🇺🇸 Sacramento, California, United States

Medical Corporation; 🇺🇸 Santa Barbara, California, United States

Stanford Healthcare; 🇺🇸 Stanford, California, United States

University of Colorado Hospital; 🇺🇸 Aurora, Colorado, United States

UConn Health/Clinical Research Center; 🇺🇸 Farmington, Connecticut, United States

Winchester Center for Lung Disease; 🇺🇸 New Haven, Connecticut, United States

The George Washington University Medical Faculty Associates; 🇺🇸 Washington, District of Columbia, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Piedmont Physicians Pulmonary & Sleep Medicine of Buckhead; 🇺🇸 Atlanta, Georgia, United States

Emory University; 🇺🇸 Atlanta, Georgia, United States

Northside Hospital Laboratory - Atlanta; 🇺🇸 Atlanta, Georgia, United States

Northwestern Memorial Hospital, Clinical Research Unit; 🇺🇸 Chicago, Illinois, United States

UI Health Hospital; 🇺🇸 Chicago, Illinois, United States

University of Iowa Hospitals & Clinics; 🇺🇸 Iowa City, Iowa, United States

University of Kansas Medical Center; 🇺🇸 Kansas City, Kansas, United States

Norton Hospital; 🇺🇸 Louisville, Kentucky, United States

Ochsner Medical Center; 🇺🇸 New Orleans, Louisiana, United States

University of Maryland Medical Center; 🇺🇸 Baltimore, Maryland, United States

Tufts Medical Center; 🇺🇸 Boston, Massachusetts, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

M Health Fairview University of Minnesota Medical Center - East Bank; 🇺🇸 Minneapolis, Minnesota, United States

University of Missouri; 🇺🇸 Columbia, Missouri, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

University of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States

University of New Mexico Health Sciences Center; 🇺🇸 Albuquerque, New Mexico, United States

NYU Langone Health; 🇺🇸 New York, New York, United States

University of Rochester Medical Center; 🇺🇸 Rochester, New York, United States

UNC Hospitals; 🇺🇸 Chapel Hill, North Carolina, United States

Duke University Medical Center - Duke South; 🇺🇸 Durham, North Carolina, United States

University of Cincinnati Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Cleveland Clinic Foundation; 🇺🇸 Cleveland, Ohio, United States

The Ohio State University Wexner Medical Center; 🇺🇸 Columbus, Ohio, United States

INTEGRIS Cardiovascular Physicians, LLC; 🇺🇸 Oklahoma City, Oklahoma, United States

Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

The Hospital of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Temple Heart and Vascular Institute (Outpatient Clinic); 🇺🇸 Philadelphia, Pennsylvania, United States

Allegheny General Hospital; 🇺🇸 Pittsburgh, Pennsylvania, United States

UPMC Presbyterian Hospital; 🇺🇸 Pittsburgh, Pennsylvania, United States

Rhode Island Hospital; 🇺🇸 Providence, Rhode Island, United States

Medical University of South Carolina - Nexus Research Center; 🇺🇸 Charleston, South Carolina, United States

Baylor University Medical Center; 🇺🇸 Dallas, Texas, United States

UT Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

CHI St. Luke's Health Baylor College of Medicine Medical Center; 🇺🇸 Houston, Texas, United States

Houston Methodist Outpatient Center; 🇺🇸 Houston, Texas, United States

Baylor Scott & White Medical Center - The Heart Hospital; 🇺🇸 Plano, Texas, United States

University of Texas Health Science Center at San Antonio; 🇺🇸 San Antonio, Texas, United States

Intermountain Medical Center; 🇺🇸 Murray, Utah, United States

Inova Fairfax Medical Campus; 🇺🇸 Falls Church, Virginia, United States

Pulmonary Associates of Richmond, Inc.; 🇺🇸 Richmond, Virginia, United States

Advocate Aurora Health-Aurora St. Luke's Medical Center; 🇺🇸 Milwaukee, Wisconsin, United States

Froedtert Hospital/Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

Cardiologia Palermo; 🇦🇷 Buenos Aires, Argentina

Instituto Cardiovascular de Buenos Aires; 🇦🇷 Buenos Aires, Argentina

Instituto de Cardiologia de Corrientes Juana Francisca Cabral; 🇦🇷 Corrientes, Argentina

Hospital Privado Centro Medico de Cordóba S.A.; 🇦🇷 Córdoba, Argentina

Instituto de Investigaciones Clinicas Quilmes; 🇦🇷 Quilmes, Argentina

Sanatorio Parque S.A.; 🇦🇷 Rosario, Argentina

Instituto Medico Rio Cuarto; 🇦🇷 Río Cuarto, Argentina

Hospital Provincial Dr. José María Cullen; 🇦🇷 Santa Fe, Argentina

Macquarie University; 🇦🇺 North Ryde, New South Wales, Australia

St Vincent's Hospital; 🇦🇺 Melbourne, Victoria, Australia

Wesley Research Institute; 🇦🇺 Auchenflower, Australia

Royal Hobart Hospital; 🇦🇺 Hobart, Australia

Nepean Hospital; 🇦🇺 Kingswood, Australia

Religious Hospital Linz GmbH; 🇦🇹 Linz, Austria

AKH-Vienna Medical Univesity of Vienna Internal Medicine II-Cardiology; 🇦🇹 Vienna, Austria

Hôpital Erasme; 🇧🇪 Anderlecht, Belgium

University Hospitals of Leuven (Campus Gasthuisberg); 🇧🇪 Leuven, Belgium

Instituto das Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa; 🇧🇷 Belo Horizonte, Brazil

Complexo de Prevencao, Diagnostico, Terapia e Reabilitacao Respiratoria - Hospital Dia do Pulmao; 🇧🇷 Blumenau, Brazil

Irmandade da Santa Casa de Misericórdia de Porto Alegre; 🇧🇷 Porto Alegre, Brazil

Uniao Brasileira de Educaçao e Assistência Hospital São Lucas da PUCRS; 🇧🇷 Porto Alegre, Brazil

Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo; 🇧🇷 São Paulo, Brazil

Núcleo de Gestão de Pesquisa/Hospital São Paulo - SPDM/UNIFESP; 🇧🇷 São Paulo, Brazil

London Health Science Centre - Victoria Hospital; 🇨🇦 London, Ontario, Canada

University of Ottawa Heart Institute; 🇨🇦 Ottawa, Ontario, Canada

Peter Lougheed Center; 🇨🇦 Calgary, Canada

University Health Network; 🇨🇦 Toronto, Canada

Enroll SpA; 🇨🇱 Santiago, Region Metropolitana, Chile

Centro de Investigacion Clinica UC-CICUC; 🇨🇱 Santiago, Chile

Fundación Abood Shaio; 🇨🇴 Bogotá, Colombia

Fundación Neumologica Colombiana; 🇨🇴 Bogotá, Colombia

Institut Klinicke a Experimentalni Mediciny; 🇨🇿 Praha, Czechia

Všeobecná fakultní nemocnice v Praze Il. interní klinika kardiologie a angiologie VFN a 1.LF UK Centrum pro plicní hypertenzi; 🇨🇿 Praha, Czechia

Aarhus Universitetshospital, Department of Cardiology; 🇩🇰 Aarhus, Denmark

Rigshospitalet, Department of Cardiology; 🇩🇰 Copenhagen, Denmark

CHU Bicêtre; 🇫🇷 Le Kremlin-Bicêtre, France

Institut Coeur Poumon; 🇫🇷 Lille, France

CHU de Montpellier; 🇫🇷 Montpellier, France

Hôpital Pasteur; 🇫🇷 Nice, France

CHU de Poitiers; 🇫🇷 Poitiers, France

Hôpitaux Universitaires de Strasbourg; 🇫🇷 Strasbourg, France

Centre Hospitalier Universitaire - Hôpital d´Adultes de Brabois; 🇫🇷 Vandœuvre-lès-Nancy, France

DRK Kliniken Berlin Westend; 🇩🇪 Berlin, Germany

Universitatsklinikum Dresden, Medizinische Klinik / Pneumologisches Studiensekretariat; 🇩🇪 Dresden, Germany

Universitatsklinikum Giessen und Marburg GmbH Zentrum fur Innere Medizin, Med. Klinik und Poliklinik II Studienambulanz fur Pulmonale Hypertonie; 🇩🇪 Gießen, Germany

Universitätsklinikum Greifswald Klinik und Poliklinik für Innere Medizin B; 🇩🇪 Greifswald, Germany

Universitätsklinikum Halle (Saale) / Martin-Luther-Universität Halle- Wittenberg, Universitätsklinik und Poliklinik für Innere Medizin I; 🇩🇪 Halle, Germany

Universitätsklinikum Hamburg-Eppendorf Zentrum für Onkologie Studienzentrum Pneumologie; 🇩🇪 Hamburg, Germany

Medizinische Hochschule Hannover Klinik für Pneumologie und Infektiologie; 🇩🇪 Hannover, Germany

Thoraxklinik Heidelberg gGmbH am Universitätsklinikum Heidelberg Zentrum für pulmonale Hypertonie; 🇩🇪 Heidelberg, Germany

Universitätsklinikum des Saarlandes, Innere Medizin V - Pneumologie, Allergologie, Beatmungs- und Umweltmedizin; 🇩🇪 Homburg, Germany

Zentrum fur Pulmona le Hypertonie, Klini k Ill fur lnnere Medizin (Kardiologie, Pneumologie, lnternlstische lntensiv medizin), Herzzentrum der Universitat zu Koln; 🇩🇪 Koln, Germany

Krankenhaus Neuwittelsbach; 🇩🇪 Munich, Germany

Klinikum der LMU Medizinische Klinik und Poliklinik V; 🇩🇪 München, Germany

Klinikum Wurzburg Mitte gGmbH Medizinische Klinik mit Schwerpunkt Pneumologie und Beatmungsmedizin; 🇩🇪 Würzburg, Germany

"Evangelismos" General Hospital, 1st Department of Clinical Care & Pulmonary Hypertension Clinic; 🇬🇷 Athens, Greece

ATTIKON University Hospital, 2nd Critical Care Department; 🇬🇷 Athens, Greece

Onassis Cardiac Surgery Center; 🇬🇷 Kallithéa, Greece

AHEPA University General Hospital of Thessaloniki, 1st Cardiology Clinic; 🇬🇷 Thessaloníki, Greece

Mater Misericordiae University Hospital, Respiratory Department; 🇮🇪 Dublin, Ireland

Lady Davis Carmel Medical Center; 🇮🇱 Haifa, Israel

Meir Medical Center; 🇮🇱 Kfar Saba, Israel

Rabin Medical Center; 🇮🇱 Petach Tikva, Israel

The Chaim Sheba Medical Center; 🇮🇱 Ramat Gan, Israel

Tel Aviv Sourasky Medical Center; 🇮🇱 Tel Aviv, Israel

IRCCS Azienda Ospedaliero Universitaria Di Bologna Policlinico 5 Orsola Malpighi - U.O.C. Cardiologia; 🇮🇹 Bologna, Italy

IRCCS Ospedale Policlinico San Martino - Cardiovascular Diseases Unit - Cardiac, Thoracic and Vascular Department; 🇮🇹 Genova, Italy

Azienda Ospedaliera Dei Colli - Ospedale Monaldi Centro per la Diagnosi e Terapia dell'Ipertensione Polmonare; 🇮🇹 Napoli, Italy

Fondazione IRCCS Policlinico San Matteo - U.O. di Cardiologia; 🇮🇹 Pavia, Italy

Azienda Ospealiero Universitaria Policlinico Umberto I - Dipartamento di Scienze Cliniche Internistiche Anestesiologiche e Cardiovascolari - VIII Padglione; 🇮🇹 Rome, Italy

Azienda Sanitaria Universitaria Giuliano Isontina /ASUGI - Ospedale di Cattinara - Cardiovascular Department Coronary Intensive Care Unit; 🇮🇹 Trieste, Italy

Kyushu University Hospital; 🇯🇵 Fukuoka, Japan

Kurume University Hospital; 🇯🇵 Kurume, Japan

Nagoya University Hospital; 🇯🇵 Nagoya-Shi, Japan

NHO Okayama Medical Center; 🇯🇵 Okayama, Japan

Keio University Hospital; 🇯🇵 Shinjuku-Ku, Japan

National Cerebral and Cardiovascular Center; 🇯🇵 Suita, Japan

Kyorin University Hospital; 🇯🇵 Tokyo, Japan

University of Tokyo Hospital; 🇯🇵 Tokyo, Japan

Gachon University Gil Medical Center; 🇰🇷 Incheon, Korea, Republic of

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

Severance Hospital, Yonsei University Health System Seoul; 🇰🇷 Seoul, Korea, Republic of

The Catholic University of Korea, Seoul St. Mary´s Hospital; 🇰🇷 Seoul, Korea, Republic of

Pauls Stradins Clinical University Hospital; 🇱🇻 Riga, Latvia

Hospital of Lithuanian University of Health Sciences Kauno klinikos; 🇱🇹 Kaunas, Lithuania

Instituto nacional de Cardiologia Ignacio Chavez; 🇲🇽 Mexico City, Mexico

Hospital Universitario Dr. José Eleuterio González Centro de Prevención y Rehabilitación de Enfermedades Pulmonares Crónicas; 🇲🇽 Monterrey, Mexico

Unidad de Investigacion Clinica en Medicina, S.C.; 🇲🇽 Monterrey, Mexico

Amsterdam UMC, location VUmc; 🇳🇱 Amsterdam, Netherlands

Erasmus MC; 🇳🇱 Rotterdam, Netherlands

Krakowski Szpital Specjalistyczny Im. Św. Jana Pawła II Oddział Kliniczny Chorób Serca i Naczyń z Pododdziałem Intensywnego Nadzoru Kardiologicznego; 🇵🇱 Kraków, Poland

Europejskie Centrum Zdrowia Otwock Sp. z o.o. Szpital irn. Fryderyka Chopina Oddzial Kardiologiczny; 🇵🇱 Otwock, Poland

Centro Hospitalar e Universitário de Coimbra; 🇵🇹 Coimbra, Portugal

Centro Hospitalar Universitário Lisboa Norte, EPE - Hospital Pulido Valente; 🇵🇹 Lisboa, Portugal

Centro Hospitalar Universitário de Santo António; 🇵🇹 Porto, Portugal

Centro Hospitalar Vila Nova De Gaia; 🇵🇹 Vila Nova De Gaia, Portugal

CardioPulmonary Research Center; 🇵🇷 Guaynabo, Puerto Rico

Emergency Institute of Cardiovascular Diseases "Prof. Dr. C.C. Iliescu" Bucharest, Cardiology 2; 🇷🇴 Bucharest, Romania

"Niculae Stanciolu" Emergency Heart Institute for Cardivascular Diseases; 🇷🇴 Cluj-Napoca, Romania

Mediprax Centrum S.R.L; 🇷🇴 Cluj-Napoca, Romania

Targu-Mures Emergency Clinical County Hospital, Internal Medicine II; 🇷🇴 Târgu-Mureş, Romania

King Fahad Medical City; 🇸🇦 Riyadh, Saudi Arabia

King Faisal Specialist Hospital and Research Center; 🇸🇦 Riyadh, Saudi Arabia

Institute for Cardiovascular Diseases "Dedinje" Clinic for Cardiology; 🇷🇸 Belgrade, Serbia

University Clinical Centre of Serbia, Cardiology Clinic; 🇷🇸 Belgrade, Serbia

National Heart Centre Singapore; 🇸🇬 Singapore, Singapore

National University Heart Centre Singapore; 🇸🇬 Singapore, Singapore

Hospital Clinic I Provincial; 🇪🇸 Barcelona, Spain

Hospital Universitari Vall d'Hebron; 🇪🇸 Barcelona, Spain

Hospital Universitario 12 De Octubre; 🇪🇸 Madrid, Spain

Hospital Universitario Puerta De Hierro Majadahonda; 🇪🇸 Majadahonda, Spain

Hospital Costa del Sol; 🇪🇸 Marbella, Spain

Hospital Universitario Son Espases; 🇪🇸 Palma De Mallorca, Spain

Hospital Universitario de Salamanca (Complejo Asistencial Universitario De Salamanca); 🇪🇸 Salamanca, Spain

Hospital Universitario Marques de Valdecilla; 🇪🇸 Santander, Spain

Hospital Universitario Virgen del Rocío; 🇪🇸 Sevilla, Spain

Hospital Universitario de Toledo; 🇪🇸 Toledo, Spain

Hospital universitario Y Politecnico La Fe; 🇪🇸 Valencia, Spain

Royal Papworth Hospital NHS Foundation Trust; 🇬🇧 Cambridge, United Kingdom

Golden Jubilee National Hospital, Agamemnon Street; 🇬🇧 Clydebank, United Kingdom

Hammersmith Hospital; 🇬🇧 London, United Kingdom

Royal Brompton Hospital, Pulmonary Hypertension Service, Sydney Street; 🇬🇧 London, United Kingdom

Royal Free Hospital; 🇬🇧 London, United Kingdom

Freeman Hospital; 🇬🇧 Newcastle, United Kingdom

Sheffield Clinical Research Facility, Royal Hallamshire Hospital; 🇬🇧 Sheffield, United Kingdom