A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
- Conditions
- Pulmonary HypertensionVascular DiseasesCardiovascular DiseasesHypertension, PulmonaryPulmonary Arterial HypertensionHypertensionFamilial Primary Pulmonary HypertensionPAHConnective Tissue DiseasesLung Diseases
- Interventions
- Drug: PlaceboDrug: Ralinepag
- Registration Number
- NCT03626688
- Lead Sponsor
- United Therapeutics
- Brief Summary
Study ROR-PH-301, ADVANCE OUTCOMES, is designed to assess the efficacy and safety of ralinepag when added to pulmonary arterial hypertension (PAH) standard of care or PAH-specific background therapy in subjects with World Health Organization (WHO) Group 1 PAH.
- Detailed Description
Study ROR-PH-301 is a multicenter, randomized, double-blind, placebo-controlled study. Subjects who meet entry criteria will be randomly allocated 1:1 to receive ralinepag or placebo, in addition to their standard of care or PAH-specific background therapy, as applicable. The primary endpoint is the time (in days) from randomization to the first adjudicated protocol-defined clinical worsening event. All primary endpoint events will be adjudicated by an independent Clinical Event Committee (CEC) in a blinded fashion. Subjects who have a confirmed primary endpoint event adjudicated by the CEC at any time during the study and all subjects on treatment at the conclusion of the study who have completed the Week 28 Visit (after the target number of confirmed events is achieved) will have the option to enroll in an open-label extension (OLE) study. Subjects who do not choose to participate in the OLE study will discontinue study drug and should remain in the study for long-term follow-up of survival status and will receive standard of care PAH treatment, at the discretion of the treating physician.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1000
- At least 18 years of age.
- Evidence of a personally signed and dated informed consent form indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any study-related procedures.
- Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
- Primary diagnosis of symptomatic PAH.
- Has had a right heart catheterization (RHC) performed at or within 3 years prior to Screening (RHC will be performed during Screening if not available) that is consistent with the diagnosis of PAH.
- Has WHO/ NYHA functional class II to IV symptoms.
- If on PAH-specific background oral therapy, subject is on stable therapy with either an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 inhibitor (PDE5-I) or a soluble guanylate cyclase (sGC) stimulator.
- Has a 6MWD of ≥150 meters.
- If taking concomitant medications that may affect the clinical manifestations of PAH (eg, calcium channel blockers, diuretics, digoxin, or L arginine supplementation, beta blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers), must be on a stable dose for at least 30 days prior to the Baseline Visit and the dosage maintained throughout the study. The exception is that the dose of diuretics must be stable for at least the 10 days prior to Baseline.
- Both male and female subjects agree to use a highly effective method of birth control throughout the entire study period from informed consent through to the 30-Day Follow-up Visit, if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in a conception process during the study and for 30 days after the last dose of IMP. Eligible male subjects must agree not to participate in sperm donation for 90 days after the last dose of IMP.
- For subjects with known HIV-associated PAH, a cluster designation 4 (CD4+) T-cell count <200/mm3 within 90 days of Baseline.
- Must not have 3 or more left ventricular dysfunction risk factors as defined in the study protocol.
- Has evidence of more than mild lung disease on pulmonary function tests performed within 180 days prior to, or during Screening.
- Has evidence of thromboembolic disease as determined by a V/Q lung scan or local standard of care diagnostic evaluation at or after diagnosis of PAH.
- Current diagnosis of ongoing and clinically significant sleep apnea as defined by the Investigator.
- Male subjects with a corrected QT interval using Fridericia's formula (QTcF) >450 msec and female subjects with a QTcF >470 msec on ECG recorded at Screening and analyzed by the central ECG laboratory. Subjects with evidence of intraventricular conduction delay, defined as a QRS interval greater than 110 msec, will be excluded if the QTcF is >500 msec for both males and females.
- Severe chronic liver disease (ie, Child-Pugh Class C), portal hypertension, cirrhosis or complications of cirrhosis/portal hypertension (eg, history of variceal hemorrhage, encephalopathy).
- Confirmed active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
- Subjects with alanine aminotransferase or aspartate aminotransferase ≥3 times the upper limit of normal (ULN) or total bilirubin ≥2 × ULN at Screening.
- Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL or requiring dialysis at Screening.
- Hemoglobin concentration <9 g/dL at Screening.
- Subjects treated with an IV or SC prostacyclin pathway agent (eg, epoprostenol, treprostinil, or iloprost) for PAH at any time prior to Baseline (use in vasoreactive testing is permitted).
- Subjects currently on or who were treated with an inhaled or oral prostacyclin pathway agent (iloprost, treprostinil, beraprost, or selexipag) for >6 months or within 90 days prior to Baseline.
- Subject has pulmonary veno-occlusive disease.
- Malignancy diagnosed and/or treated within 5 years prior to Screening, with the exception of localized non-metastatic basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix excised with curative intent.
- Subject tests positive for amphetamine, cocaine, methamphetamine, methylenedioxymethamphetamine or phencyclidine in urine drug screen performed at Screening, or has a recent history (6 months) of alcohol or drug abuse. A subject will not be excluded due to a positive drug screen caused by prescribed medications.
- Initiation or discontinuation of a cardio-pulmonary rehabilitation program based upon exercise within 90 days prior to Screening and/or planned during study participation.
- Prior participation in any study of ralinepag or participation in another interventional clinical study with medicinal products within 30 days prior to Screening. Concurrent participation in registry or observational studies is allowed, as long as the subject can fulfill all other entry criteria and comply with all study procedures.
- Any reason that, in the opinion of the Investigator or Medical Monitor, precludes the subject from participating in the study (eg, any previous or intercurrent medical condition) that may increase the risk associated with study participation or that would confound study analysis or impair study participation or cooperation.
- Known hypersensitivity to ralinepag or any of the excipients.
- Life expectancy <12 months based on the Investigator's opinion.
- Women who are pregnant, lactating or breast-feeding.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Matching placebo tablets (oral) Ralinepag Ralinepag Ralinepag once daily extended-release tablets (oral) 50, 250, and 400 mcg titrated to the highest tolerated dose.
- Primary Outcome Measures
Name Time Method Time from randomization to the first adjudicated protocol-defined clinical worsening event The study duration was event-based. This parameter was assessed from randomization until the conclusion of the study, up to 3 years Clinical worsening events are defined as death, nonelective hospital admission for worsening PAH (further defined in clinical study protocol), initiation of parenteral or inhaled prostacyclin pathway agent for treatment of worsening PAH, disease progression (further defined in clinical study protocol), or unsatisfactory long-term clinical response (further defined in clinical study protocol).
- Secondary Outcome Measures
Name Time Method Change from Baseline in 6-minute walk distance (6MWD) Baseline to Week 28 6MWD was measured at Baseline (prior to starting study drug) and Week 4, 8, 12, and 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.
Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) risk score Baseline to Week 28 Data from NT-proBNP, 6MWD, WHO/NYHA functional class, systolic blood pressure, heart rate, and estimated glomerular filtration rate values collected at visits through Week 28 were used to calculate the composite REVEAL risk score.
Time to first all-cause nonelective hospitalization The study duration was event-based. This parameter was assessed from randomization until the conclusion of the study (when the target number of adjudicated events was achieved, as defined in the study protocol). All nonelective hopsitalizations during the study period were collected.
Change from Baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) Baseline to Week 28 NT-proBNP was measured at Baseline (prior to starting study drug) and Week 4, 8, 12, and 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.
Change from Baseline in WHO/New York Heart Association (NYHA) Functional Class Baseline to Week 28 The severity of PAH was graded according to the functional status of the subject and assessed at every visit.
Shift and proportion of subjects who attain all 3 of the following: NT-proBNP level <300 pg/mL, 6MWD >440 meters, and WHO/NYHA Functional Class I or II Baseline to Week 28 Data from NT-proBNP, 6MWD, and WHO/NYHA functional class assessment were compiled as a composite endpoint at visits through Week 28.
Clinical improvement as defined by the absence of clinical worsening and fulfillment of at least 2 of the 3 of the following: increase in 6MWD ≥10% or ≥30 m, improvement to or maintenance of WHO FC I or II, and decrease in NT-proBNP by at least 30%. Baseline to Week 28 Data from 6MWD, WHO/NYHA functional class assessment, and NT-proBNP were compiled as a composite endpoint at visits through Week 28.
Safety and tolerability of ralinepag in subjects with PAH Baseline to Week 28 Safety and tolerability were assessed by adverse events.
Change from Baseline in health-related quality of life as measured by patient-reported outcomes. Baseline to Week 28 Quality of life was assessed using patient-reported outcomes at Baseline (prior to starting study drug) and Week 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.
Time to all-cause mortality The study duration was event-based. This parameter was assessed from randomization until the conclusion of the study (when the target number of adjudicated events was achieved, as defined in the study protocol). All deaths during the study period were collected.
Change from Baseline in heart rate recovery (HRR) following completion of the 6MWT Baseline to Week 28 HRR was measured at Baseline (prior to starting study drug) and Week 4, 8, 12, and 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.
Trial Locations
- Locations (214)
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
St. Joseph's Hospital and Medical Center
🇺🇸Phoenix, Arizona, United States
Mayo Clinic Scottsdale
🇺🇸Scottsdale, Arizona, United States
University of Arizona
🇺🇸Tucson, Arizona, United States
UCSD Health Sciences
🇺🇸La Jolla, California, United States
Loma Linda University Medical Center
🇺🇸Loma Linda, California, United States
Ronald Reagan UCLA Medical Center
🇺🇸Los Angeles, California, United States
Kaiser Permanente Los Angeles Medical Center
🇺🇸Los Angeles, California, United States
Keck Hospital of USC
🇺🇸Los Angeles, California, United States
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
VA Greater Los Angeles Healthcare System
🇺🇸Los Angeles, California, United States
University of California, Irvine
🇺🇸Orange, California, United States
University of California Davis Medical Center
🇺🇸Sacramento, California, United States
SBPA Research LLC
🇺🇸Santa Barbara, California, United States
Stanford Healthcare
🇺🇸Stanford, California, United States
LA Biomedical Research Institute Harbor-UCLA Medical Center
🇺🇸Torrance, California, United States
University of Colorado Hospital
🇺🇸Aurora, Colorado, United States
National Jewish Health
🇺🇸Denver, Colorado, United States
University of Florida
🇺🇸Gainesville, Florida, United States
Mayo Clinic Florida
🇺🇸Jacksonville, Florida, United States
University of Miami
🇺🇸Miami, Florida, United States
Central Florida Pulmonary Group
🇺🇸Orlando, Florida, United States
AdventHealth Orlando
🇺🇸Orlando, Florida, United States
Cleveland Clinic Florida
🇺🇸Weston, Florida, United States
Emory University Hospital
🇺🇸Atlanta, Georgia, United States
Piedmont Healthcare Pulmonary and Critical Care Research
🇺🇸Austell, Georgia, United States
University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
Ascension Alexian Brothers
🇺🇸Elk Grove Village, Illinois, United States
Indiana University School of Medicine
🇺🇸Indianapolis, Indiana, United States
Community Health Network Cancer Center North
🇺🇸Indianapolis, Indiana, United States
St. Vincent Medical Group, Inc.
🇺🇸Indianapolis, Indiana, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
Kentuckiana Pulmonary Research Center
🇺🇸Louisville, Kentucky, United States
Ochsner Medical Center
🇺🇸New Orleans, Louisiana, United States
Chest Medicine Associates
🇺🇸South Portland, Maine, 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
Boston University Medical Center
🇺🇸Boston, Massachusetts, United States
Spectrum Health Medical Group
🇺🇸Grand Rapids, Michigan, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
University of New Mexico
🇺🇸Albuquerque, New Mexico, United States
Winthrop Hospital
🇺🇸Mineola, New York, United States
NYU Langone Medical Center
🇺🇸New York, New York, United States
Weill-Cornell-New York Presbyterian Hospital
🇺🇸New York, New York, United States
Mount Sinai School of Medicine
🇺🇸New York, New York, United States
University of Rochester
🇺🇸Rochester, New York, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
East Carolina University
🇺🇸Greenville, North Carolina, United States
University of Cincinnati-Medical Science Building
🇺🇸Cincinnati, Ohio, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
The Ohio State University Wexner Medical Center
🇺🇸Columbus, Ohio, United States
Integris Baptist Medical Center
🇺🇸Oklahoma City, Oklahoma, United States
Oregon Clinic-Pulmonary West
🇺🇸Portland, Oregon, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Temple University
🇺🇸Philadelphia, Pennsylvania, United States
Allegheny General Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
Statcare Pulmonary Consultants
🇺🇸Knoxville, Tennessee, United States
Ascension Texas Cardiovascular
🇺🇸Austin, Texas, United States
Baylor University Medical Center
🇺🇸Dallas, Texas, United States
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Memorial Hermann Hospital
🇺🇸Houston, Texas, United States
The Methodist Hospital Research Institute
🇺🇸Houston, Texas, United States
Vermont Lung Center
🇺🇸Colchester, Vermont, United States
University of Virginia Medical Center
🇺🇸Charlottesville, Virginia, United States
Sentara Cardiovascular Research Institute
🇺🇸Norfolk, Virginia, United States
Carilion Clinic Pulmonary and Sleep Medicine
🇺🇸Roanoke, Virginia, United States
Medical College of Wisconsin/Froedtert Hospital
🇺🇸Milwaukee, Wisconsin, United States
Hospital Italiano
🇦🇷Ciudad Autonoma Buenos Aires, Buenos Aires, Argentina
Instituto de Investigaciones Clinicas Mar del Plata
🇦🇷Mar Del Plata, Buenos Aires, Argentina
Sanatorio Parque S.A.
🇦🇷Rosario, Santa Fe, Argentina
Sanatorio de la Trinidad Mitre
🇦🇷Buenos Aires, Argentina
Cardiologia Palmero
🇦🇷Caba, Argentina
Hospital Britanico de Buenos Aires
🇦🇷Ciudad Autonoma Buenos Aires, Argentina
Fundacion Respirar
🇦🇷Ciudad Autonoma Buenos Aires, Argentina
Fundacion Favaloro
🇦🇷Ciudad Autonoma Buenos Aires, Argentina
Hospital Italiano de Cordoba
🇦🇷Cordoba, Argentina
Hospital Privado Centro Medico de Cordoba S.A
🇦🇷Cordoba, Argentina
Instituto de Cardiologia de Corrientes
🇦🇷Corrientes, Argentina
Hospital PROVINCIAL "Dr. Jose Maria Cullen"
🇦🇷Santa Fe, Argentina
Royal Prince Alfred Hospital
🇦🇺Camperdown, New South Wales, Australia
St Vincent's Hospital Sydney
🇦🇺Darlinghurst, New South Wales, Australia
Nepean Hospital
🇦🇺Kingswood, New South Wales, Australia
Macquarie University
🇦🇺Macquarie, New South Wales, Australia
Westmead Hospital
🇦🇺Sydney, New South Wales, Australia
The Prince Charles Hospital
🇦🇺Chermside, Queensland, Australia
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
Royal Hobart Hospital
🇦🇺Hobart, Tasmania, Australia
St Vincent's Hospital Melbourne
🇦🇺Fitzroy, Victoria, Australia
The Alfred Hospital
🇦🇺Melbourne, Victoria, Australia
Fiona Stanley Hospital
🇦🇺Murdoch, Western Australia, Australia
Medizinische Universität Innsbruck
🇦🇹Innsbruck, Austria
Ordensklinikum Linz GmbH - Elisabethinen, Fadingerstrasse 1
🇦🇹Linz, Austria
AKH Wien, Innere Med. II, Kardiologie, Währingergürtel 18-20
🇦🇹Vienna, Austria
Cliniques Universitaires de Bruxelles Hopital Erasme
🇧🇪Bruxelles, Belgium
UZ Leuven, UZ Leuven Campus Gasthuisberg, Herestraat 49
🇧🇪Leuven, Belgium
HC-UFG - Hospital das Clínicas da Universidade Federal de Goiás
🇧🇷Goiânia, Goias, Brazil
Instituto das Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa
🇧🇷Belo Horizonte, MG, Brazil
Hospital Sao Lucas da PUC-RS
🇧🇷Porto Alegre, R.S, Brazil
Irmandade da Santa Casa de Misericórdia de Porto Alegre
🇧🇷Porto Alegre, RS, Brazil
UNESP-Faculdade de Medicina da Universidade Estadual Paulista Campus Botucatu
🇧🇷Botucatu, Sao Paulo, Brazil
Hospital Sao Paulo
🇧🇷Sao Paulo, SP, Brazil
Instituto do Coracao
🇧🇷Sao Paulo, SP, Brazil
MHAT - "National Heart Hospital" EAD, 65, Konyovitza Str.
🇧🇬Sofia, Bulgaria
MHAT "Sveta Anna" Sofia AD
🇧🇬Sofia, Bulgaria
Peter Lougheed Centre
🇨🇦Calgary, Alberta, Canada
LHSC - Victoria Hospital
🇨🇦London, Ontario, Canada
University Health Network-Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
SMBD Jewish General Hospital d/b/a Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Institut Universitaire de Cardiologie et de Pneumologie de Quebec
🇨🇦Québec, Quebec, Canada
Instiuto Nacional del Torax
🇨🇱Providencia, Santiago De Chile, Chile
Beijing Shijitan Hospital, Capital Medical University
🇨🇳Beijing, Beijing, China
Guangdong Provincial People's Hospital
🇨🇳Guangzhou, Guangdong, China
Xiangya Hospital Central South University
🇨🇳Changsha, Hunan, China
Shanghai Pulmonary Hospital
🇨🇳Shanghai, Shanghai, China
Fuwai Hospital, Chinese Academy of Medical Sciences
🇨🇳Beijing, China
Fuwai Central China Cardiovascular Hospital
🇨🇳Zhengzhou, China
Clinical Hospital Dubrava Zagreb, Avenija G.Šuška 6
🇭🇷Zagreb, Croatia
University Clinic for Pulmonary Diseases, Jordanovac 104
🇭🇷Zagreb, Croatia
Vseobecna fakultni nemocnice v Praze, II. interni klinika kardiologie a angiologie VFN a 1. LF UK, U nemocnice 2
🇨🇿Praha 2, Czechia
Copenhagen University Hospital (Rigshospitalet)
🇩🇰Copenhagen, Denmark
Århus Universitetshospital
🇩🇰Århus, Denmark
CHU de Strasbourg - Nouvel Hôpital Civil, Ctre de competence Hypertension Arterielle Pulmona, 1 place de l Hopital
🇫🇷Strasbourg, Bas Rhin, France
CHU de Grenoble - Hôpital Albert Michallon, Clinique de Cardiologie, Boulevrad de la Chantourne
🇫🇷Grenoble, Isere, France
CHU de Saint-Etienne - Hopital Nord, Service de Medecine vasculaire et therapeutique, 81 Avenue A. Raimond
🇫🇷Saint-Étienne, Loire, France
CHU Nancy - Hôpital de Brabois Adultes, Pneumologie- Oncologie Médicale, Rue du Morvan
🇫🇷Vandoeuvre les Nancy, Meurthe Et Moselle, France
CHU Lyon - Hôpital Cardio-Vasculaire et Pneumologique Louis Pradel, Service de Pneumologie, 59 Boulevard Pinel
🇫🇷Bron cedex, Rhone, France
CHU de Rouen - Hôpital Charles Nicolle
🇫🇷Rouen cedex, Seine Maritime, France
Groupement Hospitalier Sud - Hôpital Bicêtre
🇫🇷Le Kremlin-Bicêtre, Val De Marne, France
CHU Besançon - Hôpital Jean Minjoz
🇫🇷Besançon Cedex, France
CHU de Brest - Hôpital de la Cavale Blanche
🇫🇷Brest cedex 2, France
CHRU de Lille - Hopital Cardiologique
🇫🇷Lille Cedex, France
Hôpital Nord - CHU Marseille
🇫🇷Marseille, France
Thoraxklinik-Heidelberg Zentrum für Pulmonale Hypertonie
🇩🇪Heidelberg, Baden-Württemberg, Germany
Universitätsmedizin Greifswald
🇩🇪Greifswald, Mecklenburg-Vorpommern, Germany
Universitaetsmedizin der Johannes-Gutenberg-Universitaet Mainz, Zentrum für Kardiologie I, Centrum für Thrombose und Hämostase (CTH), Langenbeckstrasse 1
🇩🇪Mainz, Rheinland Pfalz, Germany
Universitaetsklinikum des Saarlandes, Innere Medizin V, IMED, Kirrberger Strasse 100, Gebäude 41
🇩🇪Homburg, Saarland, Germany
Universitätsklinikum Leipzig, Medizinische Klinik II, Pneumologie
🇩🇪Leipzig, Sachsen, Germany
Schwarzwald-Baar Klinikum
🇩🇪Donaueschingen, Germany
Universitaetsklinikum Carl Gustav Carus TU Dresden
🇩🇪Dresden, Germany
Universitaetsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
"Onasseio" Cardiosurgery Hospital, Hemodynamic Research and Interventional Cardiology Dept., 356, Syggrou Avenue
🇬🇷Athens, Kallithea, Greece
University General Hospital of Alexandroupolis
🇬🇷Alexandroupolis, Greece
University General Hospital Attikon
🇬🇷Chaidari, Greece
AHEPA General Hospital of Thessaloniki, A' Cardiology Clinic, 1 St. Kyriakidi Street
🇬🇷Thessaloniki, Greece
Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ Családorvosi Intézet és Rendelő
🇭🇺Szeged, Csongrád-Csanád, Hungary
Gottsegen György Országos Kardiovaszkuláris Intézet
🇭🇺Budapest, Hungary
Pecsi Tudomanyegyetem, Szivgyogyaszati Klinika, Ifjusag u. 13.
🇭🇺Pecs, Hungary
The Lady Davis Carmel Medical Center, 7 Michal st.
🇮🇱Haifa, Israel
Hadassah Ein Kerem Medical Center, Kiryat Hadassah
🇮🇱Jerusalem, Israel
Meir Medical Center, 59 Tshernichovski st.
🇮🇱Kfar- Sava, Israel
Rabin Medical Center-Beilinson Campus, Pulmonary Institute, 39 Jabotinsky St Ground floor
🇮🇱Petach Tikva, Israel
Tel Aviv Sourasky Medical Center, 6 Weizmann St.
🇮🇱Tel Aviv, Israel
Istituto Mediterraneo Trapianti e Terapie a Alta Specializzazione (IRCCS-ISMETT)
🇮🇹Palermo, PA, Italy
Azienda Ospedaliero Universitaria Ospedali Riuniti di Foggia, S.C. di Cardiologia, Viale Luigi Pinto, 1
🇮🇹Foggia, Italy
IRCC Ospedale Policlinico San Martino
🇮🇹Genova, Italy
Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35
🇮🇹Milano, Italy
Azienda Socio Sanitaria Territoriale di Monza (Presidio San Gerardo)
🇮🇹Monza, Italy
Fondazione IRCCS Policlinico San Matteo
🇮🇹Pavia, Italy
Azienda Ospedaliera Universitaria Policlinico Umberto I - Università di Roma La Sapienza, Viale del Policlinico, 155
🇮🇹Roma, Italy
Samsung Medical Center
🇰🇷Seoul, Gangnam-gu, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Jongno-gu, Korea, Republic of
Gachon University Hospital Gil Medical Center
🇰🇷Incheon, Namdong-gu, Korea, Republic of
Instituto Nacional de Cardiologia Dr Ignacio Chavez Rivera
🇲🇽Mexico, Distrito Federal, Mexico
Instituto Nacional de Ciencias Médicas y Nutricion Dr. Salvador Zubiran
🇲🇽Mexico, Distrito Federal, Mexico
CICUM San Miguel
🇲🇽Guadalajara, Jalisco, Mexico
Unidad de Investigacion Clinica en Medicina, S.C.
🇲🇽Monterrey, N.l., Mexico
VU Medisch Centrum, De Boelelaan 1117
🇳🇱Amsterdam, Netherlands
Uniwersytecki Szpital Kliniczny w Bialymstoku, Klinika Kardiologii z Oddzialem Intensywnego Nazdoru Kardiologicznego, M. Sklodowskiej 24a
🇵🇱Bialystok, Poland
Krakowski Szpital Specjalistyczny im. Jana Pawla II, Oddział Kliniczny Chorób Serca i Naczyń z Pododdziałem Intensywnego Nadzoru Kardiologicznego, Pradnicka 80
🇵🇱Krakow, Poland
NZOZ Europejskie Centrum Zdrowia, ul. Borowa 14/18
🇵🇱Otwock, Poland
Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu, Oddzial Kardiologii - F, ul. Dluga 1/2
🇵🇱Poznan, Poland
Premium Clinic Wrocław CM, Podwale 83/17
🇵🇱Wroclaw, Poland
Hospital Garcia de Orta, E.P.E
🇵🇹Almada, Portugal
Centro Hospitalar e Universitário de Coimbra, E.P.E.
🇵🇹Coimbra, Portugal
Centro Hospitalar Universitário Lisboa Norte, E.P.E. Hospital Pulido Valente
🇵🇹Lisboa, Portugal
Centro Hospitalar de Santo António E.P.E.
🇵🇹Porto, Portugal
Institutul de Urgenta pentru Boli Cardiovasculare "Prof. Dr. C.C. Iliescu", Sos. Fundeni nr. 258
🇷🇴Bucharest, Romania
Institutul de Pneumoftiziologie "Marius Nasta", Sos. Viilor nr. 90, Sector 5
🇷🇴Bucuresti, Romania
Institutul Inimii "Niculae Stancioiu" Cluj-Napoca, Cardiologie, Str. Motilor nr. 19-21
🇷🇴Cluj-Napoca, Romania
Spitalul Clinic de Boli Infectioase si Pneumoftiziologie "Dr. Victor Babes" Timisoara, Str. Gheorghe Adam nr. 13
🇷🇴Timisoara, Romania
Clinical Center of Serbia, Koste Todorovica 8
🇷🇸Belgrade, Serbia
Clinical Center Zemun. Clinic for internal medicine, Department of Cardiology
🇷🇸Belgrade, Serbia
Institute for Pulmonary Diseases of Vojvodina, Put Dr Goldmana 4
🇷🇸Sremska Kamenica, Serbia
National University Hospital
🇸🇬Singapore, Singapore
National Heart Centre
🇸🇬Singapore, Singapore
Hospital Universitari Vall d'Hebron, Respiratory Dept., Passeig Vall d'Hebron,119-129, Neumologia
🇪🇸Barcelona, Spain
Hospital Clinic de Barcelona, C/ Villarroel, 170
🇪🇸Barcelona, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospoital Universitari i Politecnic La Fe
🇪🇸Valencia, Spain
Sahlgrenska Universitetssjukhuset
🇸🇪Göteborg, Sweden
Linköping Universitetssjukhuset
🇸🇪Linköping, Sweden
Norrlands Universitetssjukhus, Hjärtcentrum
🇸🇪Umeå, Sweden
National Cheng Kung University Hospital
🇨🇳Tainan, Taiwan
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Osmangazi Uni Medical Faculty
🇹🇷Eskişehir, Odunpazari, Turkey
Balcalı, Çukurova Üniversitesi Kardiyoloji ABD
🇹🇷Adana, Saricam, Turkey
Mersin Üniversitesi Tip Fakültesi Ciftlikköy Kampüsü
🇹🇷Mersin, Yenisehir, Turkey
Gazi University Medical Faculty Hospital
🇹🇷Ankara, Turkey
Uludag Universitesi Tip Fakültesi, Gorukle Kampusu
🇹🇷Bursa, Turkey
Marmara Universitesi Istanbul Pendik Egitim ve Arastirma Hastanesi, Fevzi Cakmak Mahallesi Muhsin Yazicioglu Cad. No: 10
🇹🇷Istanbul, Turkey
Dokuz Eylul Universitesi Tip Fakultesi, Mithatpasa caddesi Inciralti Balcova
🇹🇷Izmir, Turkey
CE Dniprop RCC&C Center of Dniprop RC Dept of Card SI DMA of MOHU, Chair of Internal Medicine 3, 28, Knyazya Volodymyra Velykogo St.
🇺🇦Dnipro, Ukraine
SI F.H.Yanovskyi National Institute of Phthisiology and Pulmonology of NAMSU, Clinical and Functional Dept, 10, Amosova St.
🇺🇦Kyiv, Ukraine
Communal Noncommercial Enterprise of Lviv Regional Council Lviv Clinical Hospital, Dept of Cardiology, D.Halytskyi Lviv NMU, Ch of Internal Medicine #1, 7, Chernihivska str.
🇺🇦Lviv, Ukraine
Royal Free London NHS Foundation Trust, Pond Street
🇬🇧London, Greater London, United Kingdom
The Newcastle upon Tyne Hospitals NHS Foundation Trust, Sir William Leech Lung Research Centre, Freeman Hospital
🇬🇧Newcastle upon Tyne, Tyne & Wear, United Kingdom
Golden Jubilee National Hospital
🇬🇧Glasgow, West Dunbartonshire, United Kingdom
Royal Brompton Hospital
🇬🇧London, United Kingdom
Imperial College Healthcare NHS Trust
🇬🇧London, United Kingdom