A Long-term Follow-up Study of Sotatercept for PAH Treatment (MK-7962-004/A011-12)

Phase 3

Recruiting

• Conditions: Pulmonary Arterial Hypertension; PAH
• Interventions: Biological: Sotatercept

• Registration Number: NCT04796337
• Lead Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

Brief Summary

This study is being conducted to assess the long-term safety, tolerability, and efficacy of sotatercept (MK-7962, formerly called ACE-011) in participants with Pulmonary Arterial Hypertension (PAH). This open-label, long-term follow-up (LTFU) study is supported by data from the PULSAR study (Phase 2, NCT03496207) in which treatment with sotatercept resulted in hemodynamic and functional improvements in the study participants, including those receiving maximal PAH therapy with double/triple drug combinations and intravenous prostacyclin.

The primary objective of this open-label, LTFU study is to evaluate the long-term safety and tolerability of sotatercept when added to background PAH therapy in adult participants with PAH who have completed prior sotatercept studies. The secondary objective is to evaluate continued efficacy in adult participants with PAH who have completed prior sotatercept studies.

Detailed Description

Participants eligible to enroll in the study will have participated in and completed the relevant study requirements of the parent PAH sotatercept clinical studies.

Study Timeline

• Study First Submitted: 2021-02-22
• Study First Submitted QC: 2021-03-11
• Study First Posted: 2021-03-12
• Study Start: 2021-05-12
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-25
• Last Update Posted: 2024-11-27
• Primary Completion: 2031-02-05
• Study Completion: 2031-02-05

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 700

Inclusion Criteria

• Have completed their current respective PAH sotatercept clinical study and its requirements, and must not have discontinued early

• Must be willing to adhere to the study visit schedule and understand and comply with all protocol requirements

• Must have the ability to understand and provide documented informed consent

• Females of childbearing potential must:

  • Have a negative pregnancy test as verified by the investigator prior to starting study drug administration; she must agree to ongoing pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug
  • If sexually active, have used, and agree to continue to use highly effective contraception in combination with a barrier method without interruption, for at least 28 days prior to starting the investigational product, during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study drug
  • Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study drug

• Male participants must:

  • Agree to use a condom, defined as a male latex condom or non latex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy
  • Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study drug

• Must agree not to participate in any other trials of investigational drugs/devices while they are enrolled in the MK-7962-004 study

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Exclusion Criteria

• Did not participate in a sotatercept PAH parent trial
• Missed more than the equivalent of 4 consecutive doses between the end of parent study and the start of this study.
• Presence of an ongoing serious adverse event (SAE) that occurred during a PAH sotatercept clinical study that is assessed to be possibly or probably related to sotatercept
• Pregnant or breastfeeding females

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sotatercept Treatment	Sotatercept	Participants rolling over from a blinded parent study will begin sotatercept at a dose of 0.3 mg/kg SC for Visit 1. Dose will escalate to 0.7 mg/kg SC at Visit 2 through remainder of the study. Participants rolling over from an unblinded parent study will continue sotatercept at their current dose and if at dose \< 0.7 mg/kg SC can titrate up to 0.7 mg/kg SC for the remainder of the study.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experience an Adverse Event (AE)	Up to approximately 50 months	AE is any untoward medical occurrence in a clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. The number of participants who experience an AE will be reported.
Number of Participants Who Discontinue Study Treatment Due to an AE	Up to approximately 50 months	AE is any untoward medical occurrence in a clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. The number of participants who discontinue study treatment due to an AE will be reported.
Number of Participants with Detectable Anti-Drug Antibodies (ADAs)	Up to approximately 50 months	ADAs will be detected in serum. The number of participants with detectable ADAs will be presented.
Laboratory parameters (Hematology): Concentration of Red Blood Cell Count, White Blood Cell Count, Platelet Count, Hemoglobin and Hematocrit	Up to approximately 50 months	Blood samples will be collected to determine concentration of red blood cell count, white blood cell count, platelet count, hemoglobin and hematocrit at designated timepoints up to approximately 50 months.
Laboratory parameters (Serum Chemistry): Concentration of Blood Urea, Creatinine, Total Bilirubin, Direct Bilirubin, AST, ALT, ALP, Sodium, Potassium, Chloride, Calcium, Phosphorous, Glucose, Magnesium, Carbon Dioxide, and Albumin	Up to approximately 50 months	Blood samples will be collected to determine concentration of blood urea, creatinine, total bilirubin, direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP, sodium, potassium, chloride, calcium, phosphorous, glucose, magnesium, carbon dioxide, and albumin at designated time points for up to approximately 50 months.
Laboratory parameter: Concentration of Follicle Stimulating Hormone (FSH)	Up to approximately 50 months	Blood samples will be collected to determine concentration of FSH level at designated time points up to approximately 50 months.
Change From Baseline in Body Weight	Baseline and up to approximately 48 months	Change from baseline in body weight will be reported at designated time points up to approximately 48 months.
Change From Baseline in Blood Pressure	Baseline and up to approximately 48 months	Change from baseline in systolic and diastolic blood pressure will be reported at designated time points up to approximately 48 months.
Change From Baseline in Electrocardiogram (ECG)	Baseline and up to approximately 48 months	Change from baseline in ECG (12-lead) for the determination of QTcF interval will be reported at designated time points up to approximately 48 months.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in 6-Minute Walk Distance (6MWD)	Baseline and up to approximately 48 months	The 6MWD was the distance walked in 6 minutes as a measure of functional capacity. This was assessed using the 6-minute walk test (6MWT). The change from baseline in 6MWD will be reported.
Change From Baseline in N-Terminal Pro-Hormone B-type Natriuretic Peptide (NT-proBNP) Levels	Baseline and up to approximately 48 months	NT-proBNP is a circulating biomarker that reflects myocardial stretch. The change from baseline in NT-proBNP level will be reported.
Change From Baseline in the Percentage of Participants Who Improve in modified New York Heart Association (NYHA)/ World Health Organization classification of functional status (WHO FC)	Baseline and up to approximately 48 months	The severity of participant's pulmonary arterial hypertension (PAH) symptoms will be graded using the WHO FC system. WHO functional classification for PAH ranges from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). Participants who improve in WHO FC were classified into "Improved", "No change" and "Worsened". Improvement = reduction in FC, worsened = increase in FC and no change = no change in FC. The change from baseline in the percentage of participants who improve in WHO FC will be reported.
Change From Baseline in Pulmonary Vascular Resistance (PVR)	Baseline and up to approximately 48 months	PVR is a hemodynamic variable of pulmonary circulation and was measured by right heart catheterization (RHC). The change from baseline in PVR will be reported.
Overall Survival (OS)	Up to approximately 116 months	Overall survival is defined as the time from the start of the first sotatercept treatment in the individual participant's parent study or in this study, if the participant was completely on placebo in the parent study, to the date of death in this study, regardless of the actual cause of the participant's death.
Change From Baseline in Percentage of Participants Who Maintain or Achieve a Low Risk Score Using the Simplified French Risk Score Calculator	Baseline and up to approximately 48 months	The simplified French risk scoring system was based on the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension (PH). In this study, the noninvasive parameters were used to determine the score. 'Low risk' was defined as attaining or maintaining all 3 low-risk criteria: WHO FC I or II, 6MWD \> 440 m, and NT-proBNP \<300 ng/L. The change from baseline in percentage of participants who maintained or achieved a low risk score using the simplified French risk score calculator will be reported.
Change From Baseline in Borg Dyspnea Scale Category Ratio 10 (Borg CR 10) Score	Baseline and up to approximately 48 months	The Borg CR 10 Scale assesses the severity of shortness of breath as perceived by the participant. Participants will be asked: How much difficulty is your breathing causing you right now?". The score of the item ranges from 0 (no difficulty in breathing) to10 (maximum difficulty in breathing). Higher score indicates more severe dyspnea. The change from baseline in Borg CR10 scale score will be reported.

Trial Locations

Locations (189)

Meir Medical Center. ( Site 1707); 🇮🇱 Kfar Saba, Israel

Kaohsiung Veterans General Hospital ( Site 3702); 🇨🇳 Kaohsiung, Taiwan

China Medical University Hospital ( Site 3701); 🇨🇳 Taichung, Taiwan

National Cheng Kung University Hospital ( Site 3703); 🇨🇳 Tainan, Taiwan

Pulmonary Associates, PA ( Site 1008); 🇺🇸 Phoenix, Arizona, United States

Arizona Pulmonary Specialists ( Site 1010); 🇺🇸 Scottsdale, Arizona, United States

University of Arizona ( Site 1006); 🇺🇸 Tucson, Arizona, United States

University of California San Diego ( Site 1002); 🇺🇸 La Jolla, California, United States

David Geffen School of Medicine at UCLA ( Site 1068); 🇺🇸 Los Angeles, California, United States

University of California Irvine ( Site 1086); 🇺🇸 Orange, California, United States

UC Davis - Medial Center ( Site 1064); 🇺🇸 Sacramento, California, United States

University of California San Francisco ( Site 1019); 🇺🇸 San Francisco, California, United States

Jeffrey S.Sager MD Medical Corporation ( Site 1060); 🇺🇸 Santa Barbara, California, United States

Harbor UCLA Medical Center ( Site 1028); 🇺🇸 Torrance, California, United States

University of Colorado Hospital ( Site 1013); 🇺🇸 Aurora, Colorado, United States

The George Washington University Medical Faculty Associates ( Site 1025); 🇺🇸 Washington, District of Columbia, United States

Mayo Clinic Jacksonville - PPDS ( Site 1045); 🇺🇸 Jacksonville, Florida, United States

AdventHealth Orlando ( Site 1058); 🇺🇸 Orlando, Florida, United States

University of South Florida ( Site 1043); 🇺🇸 Tampa, Florida, United States

Emory University ( Site 1030); 🇺🇸 Atlanta, Georgia, United States

University of Iowa Hospital and Clinics ( Site 1050); 🇺🇸 Iowa City, Iowa, United States

Norton Pulmonary Specialists ( Site 1066); 🇺🇸 Louisville, Kentucky, United States

Johns Hopkins Pulmonary and Critical Care Medicine ( Site 1036); 🇺🇸 Baltimore, Maryland, United States

Tufts Medical Center - PPDS ( Site 1012); 🇺🇸 Boston, Massachusetts, United States

Brigham & Women's Hospital ( Site 1014); 🇺🇸 Boston, Massachusetts, United States

University of Michigan ( Site 1011); 🇺🇸 Ann Arbor, Michigan, United States

University of Minnesota ( Site 1062); 🇺🇸 Minneapolis, Minnesota, United States

University of Kansas Medical Center ( Site 1020); 🇺🇸 Kansas City, Missouri, United States

Barnes-Jewish Hospital Center for Outpatient Health ( Site 1022); 🇺🇸 Saint Louis, Missouri, United States

University of Nebraska Medical Center ( Site 1053); 🇺🇸 Omaha, Nebraska, United States

Renown Regional Medical Center ( Site 1055); 🇺🇸 Reno, Nevada, United States

University of New Mexico Health Sciences Center ( Site 1048); 🇺🇸 Albuquerque, New Mexico, United States

New York Presbyterian Hospital - Weill Cornell Medical Center ( Site 1046); 🇺🇸 New York, New York, United States

University of Rochester Medical Center - PPDS ( Site 1039); 🇺🇸 Rochester, New York, United States

The University of North Carolina at Chapel Hill ( Site 1042); 🇺🇸 Chapel Hill, North Carolina, United States

Duke University Medical Center ( Site 1026); 🇺🇸 Durham, North Carolina, United States

The Lindner Center for Research and Education at The Christ Hospital ( Site 1001); 🇺🇸 Cincinnati, Ohio, United States

University of Cincinnati Medical Center ( Site 1035); 🇺🇸 Cincinnati, Ohio, United States

Cleveland Clinic Foundation ( Site 1065); 🇺🇸 Cleveland, Ohio, United States

The Ohio State University Wexner Medical Center ( Site 1032); 🇺🇸 Columbus, Ohio, United States

Integris Health, Inc. ( Site 1084); 🇺🇸 Oklahoma City, Oklahoma, United States

The Oregon Clinic Pulmonary, Critical Care and Sleep Medicine - West ( Site 1054); 🇺🇸 Portland, Oregon, United States

UPMC Presbyterian. UPMC Presbyterian Hospital ( Site 1059); 🇺🇸 Pittsburgh, Pennsylvania, United States

Rhode Island Hospital ( Site 1033); 🇺🇸 Providence, Rhode Island, United States

Medical University of South Carolina - PPDS ( Site 1003); 🇺🇸 Mount Pleasant, South Carolina, United States

Statcare Pulmonary Consultants - Knoxville ( Site 1031); 🇺🇸 Knoxville, Tennessee, United States

Vanderbilt University Medical Center ( Site 1027); 🇺🇸 Nashville, Tennessee, United States

University of Texas Southwestern Medical Center ( Site 1038); 🇺🇸 Dallas, Texas, United States

CHI St. Luke's Health Baylor College of Medicine Medical Center ( Site 1044); 🇺🇸 Houston, Texas, United States

Houston Methodist Hospital ( Site 1009); 🇺🇸 Houston, Texas, United States

University of Utah - PPDS ( Site 1049); 🇺🇸 Salt Lake City, Utah, United States

University of Washington Medical Center ( Site 1067); 🇺🇸 Seattle, Washington, United States

Froedtert Hospital & the Medical College of Wisconsin ( Site 1051); 🇺🇸 Milwaukee, Wisconsin, United States

Cardiologia Palermo ( Site 1911); 🇦🇷 Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina

Instituto de Investigaciones Clinicas Quilmes ( Site 1903); 🇦🇷 Quilmes, Buenos Aires, Argentina

Centro Medico Dra De Salvo ( Site 1904); 🇦🇷 Ciudad Autonoma de Buenos Aires, Caba, Argentina

Instituto Médico DAMIC ( Site 1909); 🇦🇷 Córdoba, Cordoba, Argentina

Instituto Medico Rio Cuarto ( Site 1907); 🇦🇷 Rio Cuarto, Cordoba, Argentina

Hospital Provincial del Centenario ( Site 1912); 🇦🇷 Rosario, Santa Fe, Argentina

Instituto Cardiovascular de Rosario ( Site 1906); 🇦🇷 Rosario, Santa Fe, Argentina

Centro Oncologico de Rosario ( Site 1905); 🇦🇷 Rosario, Santa Fe, Argentina

Hospital Universitario Austral ( Site 1901); 🇦🇷 Buenos Aires, Argentina

Sanatorio Allende ( Site 1908); 🇦🇷 Cordoba, Argentina

Hospital Dr. Jose Maria Cullen ( Site 1902); 🇦🇷 Santa Fe, Argentina

Royal Prince Alfred Hospital ( Site 1106); 🇦🇺 Camperdown, New South Wales, Australia

Saint Vincents Hospital Sydney ( Site 1102); 🇦🇺 Darlinghurst, New South Wales, Australia

John Hunter Hospital ( Site 1101); 🇦🇺 New Lambton, New South Wales, Australia

The Prince Charles Hospital ( Site 1104); 🇦🇺 Brisbane, Queensland, Australia

Princess Alexandra Hospital ( Site 1108); 🇦🇺 Woolloongabba, Queensland, Australia

Royal Adelaide Hospital ( Site 1109); 🇦🇺 Adelaide, South Australia, Australia

Royal Hobart Hospital ( Site 1107); 🇦🇺 Hobart, Tasmania, Australia

Fiona Stanley Hospital ( Site 1103); 🇦🇺 Perth, Western Australia, Australia

Ordensklinikum Linz GmbH Elisabethinen ( Site 2002); 🇦🇹 Linz, Oberosterreich, Austria

Medizinische Universität Graz ( Site 2003); 🇦🇹 Graz, Steiermark, Austria

Medizinische Universitat Innsbruck ( Site 2004); 🇦🇹 Innsbruck, Tirol, Austria

Medizinische Universitat Wien ( Site 2001); 🇦🇹 Wien, Austria

Erasme Hospital ( Site 1402); 🇧🇪 Bruxelles, Bruxelles-Capitale, Region De, Belgium

UZ Leuven - Campus Gasthuisberg ( Site 1401); 🇧🇪 Leuven, Vlaams-Brabant, Belgium

Hospital Madre Teresa ( Site 1804); 🇧🇷 Belo Horizonte, Minas Gerais, Brazil

Irmandade da Santa Casa de Misericórdia de Porto Alegre ( Site 1805); 🇧🇷 Porto Alegre, Rio Grande Do Sul, Brazil

Hospital São Lucas da PUCRS ( Site 1801); 🇧🇷 Porto Alegre, Rio Grande Do Sul, Brazil

Hospital Dia do Pulmao ( Site 1802); 🇧🇷 Blumenau, Santa Catarina, Brazil

Hospital Sao Paulo ( Site 1806); 🇧🇷 São Paulo, Sao Paulo, Brazil

Instituto do Coracao - HCFMUSP ( Site 1803); 🇧🇷 Sao Paulo, Brazil

Peter Lougheed Centre ( Site 2102); 🇨🇦 Calgary, Alberta, Canada

University of Alberta Hospital ( Site 2101); 🇨🇦 Edmonton, Alberta, Canada

St Boniface General Hospital ( Site 2106); 🇨🇦 Winnepeg, Manitoba, Canada

St. Joseph's Healthcare Hamilton ( Site 2105); 🇨🇦 Hamilton, Ontario, Canada

Sir Mortimer B Davis Jewish General Hospital ( Site 2103); 🇨🇦 Montreal, Quebec, Canada

Centro Cardiovascular Colombiano Clínica Santa María Clínica Cardio VID ( Site 3402); 🇨🇴 Medellin, Antioquia, Colombia

Fundacion Neumologica Colombiana ( Site 3403); 🇨🇴 Bogota, Cundinamarca, Colombia

Fundacion Valle del Lili ( Site 3401); 🇨🇴 Cali, Valle Del Cauca, Colombia

Centro Medico Imbanaco de Cali S.A ( Site 3404); 🇨🇴 Santiago de Cali, Valle Del Cauca, Colombia

Klinički Bolnički Centar Split ( Site 3901); 🇭🇷 Split, Splitsko-dalmatinska Zupanija, Croatia

Klinicki Bolnicki Centar Zagreb ( Site 3902); 🇭🇷 Zagreb, Zagrebacka Zupanija, Croatia

Vseobecna fakultni nemocnice v Praze-Centrum srdečního selhání ( Site 2201); 🇨🇿 Praha 2, Czechia

Institut klinicke a experimentalni mediciny (IKEM) ( Site 2202); 🇨🇿 Praha 4, Czechia

Rigshospitalet ( Site 3802); 🇩🇰 København Ø, Hovedstaden, Denmark

Aarhus Universitetshospital, Skejby ( Site 3801); 🇩🇰 Aarhus, Midtjylland, Denmark

Centre Hospitalier Universitaire de Nice - Hopital Pasteur ( Site 1311); 🇫🇷 Nice, Alpes-Maritimes, France

Hopital Civil - CHU Strasbourg ( Site 1307); 🇫🇷 Strasbourg, Bas-Rhin, France

CHU Caen Normandie ( Site 1325); 🇫🇷 Caen, Calvados, France

Hopital Cavale Blanche ( Site 1314); 🇫🇷 Brest, Finistere, France

Groupe Hospitalier Sud ( Site 1312); 🇫🇷 Pessac, Gironde, France

CHU de Toulouse - Hopital Larrey ( Site 1315); 🇫🇷 Toulouse, Haute-Garonne, France

Hôpital Arnaud de Villeneuve - CHU Montpellier ( Site 1301); 🇫🇷 Montpellier, Herault, France

C.H.U. de Tours - Hopital Bretonneau ( Site 1310); 🇫🇷 Tours, Indre-et-Loire, France

C.H.U de Grenoble - Hopital Albert Michallon ( Site 1303); 🇫🇷 La Tronche, Isere, France

Hopital Nord Laennec ( Site 1309); 🇫🇷 Nantes, Loire-Atlantique, France

Centre Hospitalier Universitaire de Saint-Etienne ( Site 1302); 🇫🇷 Saint-Priest-en-Jarez, Loire, France

CHU Angers ( Site 1313); 🇫🇷 Angers, Maine-et-Loire, France

C.H.U. de Nancy. Hopital de Brabois Adultes ( Site 1308); 🇫🇷 Vandoeuvre Les Nancy, Meurthe-et-Moselle, France

CHRU Lille ( Site 1306); 🇫🇷 Lille, Nord, France

Hôpital Louis Pradel - Service Endocrino, Diabeto, Nutrition ( Site 1317); 🇫🇷 Bron, Rhone-Alpes, France

CHU - Hopital de Bicetre ( Site 1304); 🇫🇷 Le Kremlin Bicetre, Val-de-Marne, France

CHU de la Miletrie Poitiers ( Site 1316); 🇫🇷 Poitiers, Vienne, France

Thoraxklinik-Heidelberg gGmbH ( Site 1509); 🇩🇪 Heidelberg, Baden-Wurttemberg, Germany

Krankenhaus Neuwittelsbach ( Site 1510); 🇩🇪 München, Bayern, Germany

Universitaetsklinik Regensburg ( Site 1503); 🇩🇪 Regensburg, Bayern, Germany

Universitätsklinikum Gießen und Marburg GmbH ( Site 1512); 🇩🇪 Gießen, Hessen, Germany

Medizinische Hochschule Hannover ( Site 1505); 🇩🇪 Hannover, Niedersachsen, Germany

Universitätsklinik Köln ( Site 1511); 🇩🇪 Cologne, Nordrhein-Westfalen, Germany

Universataet des Saarlandes ( Site 1513); 🇩🇪 Homburg, Saarland, Germany

Universitätsklinikum Halle ( Site 1502); 🇩🇪 Halle, Sachsen-Anhalt, Germany

Universitaetsklinikum Carl Gustav Carus der TU Dresden ( Site 1501); 🇩🇪 Dresden, Sachsen, Germany

Universitatsklinikum Leipzig ( Site 1508); 🇩🇪 Leipzig, Sachsen, Germany

DRK Kliniken Berlin Westend ( Site 1507); 🇩🇪 Berlin, Germany

Attikon University General Hospital of Athens ( Site 3604); 🇬🇷 Athens, Attiki, Greece

Onassis Cardiac Surgery Center ( Site 3602); 🇬🇷 Athens, Attiki, Greece

Evangelismos General Hospital of Athens ( Site 3605); 🇬🇷 Athina, Attiki, Greece

AHEPA University General Hospital of Thessaloniki ( Site 3601); 🇬🇷 Thessaloniki, Greece

Assuta Ashdod Medical Center ( Site 1710); 🇮🇱 Ashdod, Israel

Barzilai Medical Center ( Site 1708); 🇮🇱 Ashkelon, Israel

Lady Davis Carmel Medical Center ( Site 1705); 🇮🇱 Haifa, Israel

Hadassah Medical Center ( Site 1711); 🇮🇱 Jerusalem, Israel

Rabin Medical Center ( Site 1703); 🇮🇱 Petach Tikvah, Israel

Sheba MC ( Site 1701); 🇮🇱 Ramat Gan, Israel

Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) ( Site 2405); 🇮🇹 Trieste, Friuli-Venezia Giulia, Italy

Ospedale S. Giuseppe Multimedica ( Site 2403); 🇮🇹 Milano, Lombardia, Italy

Fondazione IRCCS San Gerardo dei Tintori - ASST di Monza - A. O. San Gerardo ( Site 2406); 🇮🇹 Monza, Lombardia, Italy

Azienda Ospedaliera dei Colli V. Monaldi ( Site 2407); 🇮🇹 Napoli, Italy

Universita "La Sapienza" Policlinico Umberto I ( Site 2402); 🇮🇹 Roma, Italy

Chonnam National University Hospital ( Site 3105); 🇰🇷 Gwangju, Kyonggi-do, Korea, Republic of

Gachon University Gil Medical Center ( Site 3103); 🇰🇷 Incheon, Korea, Republic of

Seoul National University Hospital ( Site 3102); 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center ( Site 3106); 🇰🇷 Seoul, Korea, Republic of

The Catholic University Seoul St. Mary's Hospital ( Site 3104); 🇰🇷 Seoul, Korea, Republic of

Instituto Nacional de Cardiologia Ignacio Chavez ( Site 2503); 🇲🇽 Ciudad de Mexico, Distrito Federal, Mexico

Hospital Universitario ""Dr. Jose Eleuterio Gonzalez"" ( Site 2504); 🇲🇽 Monterrey, Nuevo Leon, Mexico

Unidad de Investigación Clínica en Medicina, S.C ( Site 2505); 🇲🇽 Sertoma, Nuevo Leon, Mexico

Hospital Angeles Lomas ( Site 2501); 🇲🇽 Huixquilucan, Mexico

Radboud University Nijmegen Medical Centre ( Site 2605); 🇳🇱 Nijmegen, Gelderland, Netherlands

Maastricht University Medical Center ( Site 2603); 🇳🇱 Maastricht, Limburg, Netherlands

VU Medisch Centrum ( Site 2601); 🇳🇱 Amsterdam, Noord-Holland, Netherlands

Erasmus MC ( Site 2604); 🇳🇱 Rotterdam, Zuid-Holland, Netherlands

Waikato District Health Board ( Site 2702); 🇳🇿 Hamilton, Waikato, New Zealand

Greenlane Clinical Centre ( Site 2703); 🇳🇿 Auckland, New Zealand

Krakowski Szpital Specjalistyczny im. Jana Pawla II ( Site 2801); 🇵🇱 Krakow, Malopolskie, Poland

Europejskie Centrum Zdrowia Otwock Szpital im Fryderyka Chopina ( Site 2802); 🇵🇱 Otwock, Mazowieckie, Poland

Hospital Garcia de Orta ( Site 3501); 🇵🇹 Almada, Setubal, Portugal

Centro Hospitalar E Universitário De Coimbra ( Site 3502); 🇵🇹 Coimbra, Portugal

Centro Hospitalar Lisboa Norte E.P.E. - Hospital Pulido Valente ( Site 3503); 🇵🇹 Lisboa, Portugal

Institute for pulmonary diseases of Vojvodina ( Site 2906); 🇷🇸 Sremska kamenica, Juznobacki Okrug, Serbia

University Clinical Center Nis ( Site 2904); 🇷🇸 Nis, Nisavski Okrug, Serbia

Clinical Center Kragujevac ( Site 2905); 🇷🇸 Kragujevac, Sumadijski Okrug, Serbia

Clinical Center of Serbia ( Site 2901); 🇷🇸 Beograd, Serbia

Institute of Cardiovascular Diseases Dedinje ( Site 2903); 🇷🇸 Beograd, Serbia

Hospital Universitario Marques de Valdecilla ( Site 1601); 🇪🇸 Santander, Cantabria, Spain

Hospital Universitario de Son Espases ( Site 1611); 🇪🇸 Palma de Mallorca, Islas Baleares, Spain

Hospital Universitario Puerta de Hierro-Majadahonda ( Site 1604); 🇪🇸 Majadahonda, Madrid, Spain

Hospital Universitari Vall d'Hebron ( Site 1605); 🇪🇸 Barcelona, Spain

Hospital Clinic de Barcelona ( Site 1602); 🇪🇸 Barcelona, Spain

Hospital Universitario Ramon y Cajal ( Site 1609); 🇪🇸 Madrid, Spain

Hospital Universitario 12 de Octubre ( Site 1603); 🇪🇸 Madrid, Spain

Hospital Universitario La Paz ( Site 1610); 🇪🇸 Madrid, Spain

Hospital Universitario de Salamanca - Complejo Asistencial Universitario de Salamanca ( Site 1608); 🇪🇸 Salamanca, Spain

Hospital Universitario de Toledo ( Site 1607); 🇪🇸 Toledo, Spain

Skanes Universitetssjukhus Lund ( Site 3203); 🇸🇪 Lund, Skane Lan, Sweden

Akademiska Sjukhuset [Uppsala, Sweden] ( Site 3204); 🇸🇪 Uppsala, Uppsala Lan, Sweden

Norrlands Universitetssjukhus ( Site 3205); 🇸🇪 Umea, Vasterbottens Lan, Sweden

Sahlgrenska Universitetssjukhuset ( Site 3201); 🇸🇪 Goteborg, Vastra Gotalands Lan, Sweden

Universitaetsspital Zurich ( Site 3301); 🇨🇭 Zurich, Switzerland

Royal Papworth Hospital ( Site 1208); 🇬🇧 Cambridge, Cambridgeshire, United Kingdom

Royal Brompton Hospital ( Site 1206); 🇬🇧 London, England, United Kingdom

Golden Jubilee National Hospital ( Site 1204); 🇬🇧 Glasgow, Glasgow City, United Kingdom

Royal Free London NHS Foundation Trust ( Site 1202); 🇬🇧 London, London, City Of, United Kingdom

Imperial College Healthcare NHS Trust ( Site 1203); 🇬🇧 London, London, City Of, United Kingdom

Royal Hallamshire Hospital ( Site 1207); 🇬🇧 Sheffield, North Yorkshire, United Kingdom

The Newcastle Upon Tyne NHS Foundation Trust ( Site 1205); 🇬🇧 Newcastle Upon Tyne, United Kingdom