Phase III Clinical Worsening Study of UT-15C in Subjects With PAH Receiving Background Oral Monotherapy
- Conditions
- Pulmonary Arterial Hypertension
- Interventions
- Drug: Treprostinil DiolamineDrug: Placebo
- Registration Number
- NCT01560624
- Lead Sponsor
- United Therapeutics
- Brief Summary
This is an international, multicenter, randomized, double-blind, placebo-controlled, event driven study in subjects with pulmonary arterial hypertension.
- Detailed Description
Study TDE-PH-310 is an international, multicenter, randomized (1:1 oral treprostinil (UT-15C): placebo), double-blind, placebo-controlled study in subjects with pulmonary arterial hypertension (PAH) who are receiving background oral monotherapy for PAH for at least 30 days at randomization. Subjects are randomly allocated to receive oral treprostinil extended-release tablets or placebo by a stratified randomization by type of background therapy (Strata 1: phosphodiesterase type 5 inhibitor \[PDE5-I\] or soluble guanylate cyclase \[sGC\] stimulator; Strata 2: endothelin receptor antagonist \[ERA\]. Subjects are also stratified by baseline 6-minute walk distance (6MWD) less than or equal to 350 m or greater than 350 m. Subjects receive their first dose of study drug (0.125 mg) or matching placebo on the day of randomization. Oral dosing of study drug is continued at 0.125 mg 3 times daily (TID; every 6 to 8 hours) with food. The dose (or matching placebo) is titrated throughout the study up to a maximum dose of 12 mg TID to reach and maintain a tolerated dosing regimen that provided optimal clinical benefit. Once randomized, subjects return for study visits every 4 weeks for the first 12 weeks, then every 12 weeks for the duration of the study. Subjects continue in the study until experiencing clinical worsening, the number of adjudicated events necessary for study closure occurr, or prematurely discontinue participation in the study for any reason other than protocol-specified clinical worsening. At each scheduled visit, subjects undergo efficacy assessments for clinical worsening, exercise capacity (6MWD and Borg dyspnea score), WHO functional class (FC), and plasma N-Terminal pro-brain natriuretic peptide (NT-proBNP). Subjects could participate in an optional hemodynamic sub-study (assessed by RHC). Safety assessments consist of adverse events (AEs), physical examinations, vital signs, 12-lead electrocardiograms (ECGs), and clinical laboratory parameters. Patients who complete all required assessments are eligible to enter a long-term, open-label, extension study (TDE-PH-311).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 690
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Voluntarily gave informed consent to participate in the study.
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Are 18 to 75 years of age (inclusive) at Screening.
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Women of childbearing potential must practice abstinence from intercourse when in line with their preferred and usual lifestyle, or use 2 different forms of highly effective contraception for the duration of the study, and for at least 30 days after discontinuing study medication. A negative urine pregnancy test is required at Screening and Baseline prior to initiating study medication.
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Male subjects must consent to use a condom during intercourse for the duration of the study, and for at least 48 hours after discontinuing study medication.
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Have a diagnosis of symptomatic idiopathic or heritable PAH, PAH associated with connective tissue disease (CTD), PAH associated with HIV infection, PAH associated with repaired congenital systemic-to-pulmonary shunt, or PAH associated with appetite suppressant or toxin use.
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If known to be positive for HIV infection, have a CD4 lymphocyte count of at least 200 cells/mm^3 assessed at Screening and are receiving current standard of care anti retroviral or other effective medication for the treatment of HIV infection.
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Have a baseline 6MWD greater than or equal to 150 m in the absence of a concurrent injury, illness, or other confounding factor including, but not limited to, use of an aid for ambulation or connection to a nonportable machine, that would have prevented the accurate assessment of the subject's exercise capacity.
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Are optimally treated with conventional pulmonary hypertension therapy with no additions, discontinuations, or dose changes for a minimum of 10 days prior to randomization. The exceptions are the discontinuation or dose changes of anticoagulants and/or dose change of diuretics.
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Are receiving a PAH-approved oral monotherapy at a minimum dose that complies with the approved prescribing information for the product for at least 30 days prior to randomization and are receiving a stable dose for at least 10 days prior to randomization.
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Have had previously undergone a cardiac catheterization within 3 years prior to the start of Screening or during the Screening Period, and the most recent assessment documented a pulmonary artery pressure mean of at least 25 mmHg, a pulmonary capillary wedge pressure (PCWP) (or in the event a PCWP could not be reliably obtained, a left ventricular end diastolic pressure [LVEDP]) less than or equal to 15 mmHg, and absence of unrepaired congenital heart disease (other than patent foramen ovale). If a reliable PCWP or LVEDP are unable to be obtained during cardiac catheterization, subjects with clinically normal left heart function and absence of clinically relevant mitral valve disease on echocardiography are eligible for enrollment.
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Undergo echocardiography with evidence of clinically normal systolic and diastolic left ventricular function and absence of any clinically significant left sided heart disease (eg, mitral valve disease). Subjects with clinically insignificant left ventricular diastolic dysfunction due to the effects of right ventricular overload (ie, right ventricular hypertrophy and/or dilatation) are eligible.
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Have a previous ventilation perfusion lung scan, high-resolution computerized tomography scan of the chest, and/or pulmonary angiography that are consistent with the diagnosis of PAH.
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Have pulmonary function tests conducted within 6 months before Screening or during the Screening Period to confirm the following:
- Total lung capacity is at least 60%
- Forced expiratory volume at 1 second is at least 50%
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In the opinion of the Principal Investigator, is able to communicate effectively with study personnel and is considered reliable, willing, and likely to cooperate with protocol requirements, including attending all study visits.
Subject
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Is pregnant or lactating.
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Have previously received oral treprostinil.
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Have received a PGI2 (except if used during acute vasoreactivity testing) within 30 days prior to randomization or have previous intolerance or significant lack of efficacy to any PGI2 or PGI2 analogue that resulted in discontinuation or inability to titrate that therapy effectively.
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Have any background conventional therapies for PAH added, removed, or dose-adjusted within 10 days prior to randomization. The exceptions are removal or dose adjustments of anticoagulants and/or dose adjustments of diuretics.
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Receive their first dose of a PAH-approved oral monotherapy less than 30 days prior to randomization, or have their PAH-approved oral monotherapy dose changed within 10 days prior to randomization, or the subject discontinues any PAH approved therapy within 30 days prior to Screening, or the subject has previously received 2 PAH approved oral therapies at the same time (specifically, a PDE5-I, an ERA, or a sGC stimulator) concomitantly for more than 90 days cumulatively.
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Have any disease associated with PAH other than CTD, HIV infection, repaired (for at least 1 year) congenital systemic-to-pulmonary shunt, PAH associated with appetite suppressant/toxin use, or have an atrial septostomy.
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Have a current diagnosis of uncontrolled sleep apnea as defined by their physician.
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Have a history of ischemic heart disease, including a previous myocardial infarction or symptomatic coronary artery disease within 6 months prior to Screening or a history of left-sided myocardial disease as evidenced by a mean PCWP (or a LVEDP) greater than 15 mmHg or left ventricular ejection fraction less than 40% as assessed by either multigated angiogram, angiography, or echocardiography.
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Have uncontrolled systemic hypertension as evidenced by systolic blood pressure (BP) greater than 160 mmHg or diastolic BP greater than 100 mmHg.
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Have alanine aminotransferase or aspartate aminotransferase levels at least 3 times greater than the upper limit of normal, clinically significant liver disease/dysfunction, or known Child-Pugh Class C hepatic disease at Screening.
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Have any other disease or condition that would interfere with the interpretation of study assessments.
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Have a musculoskeletal disorder, is using a device to assist walking, or any disease that is likely to limit ambulation, or is connected to a machine that is nonportable.
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Have an unstable psychiatric condition or is mentally incapable of understanding the objectives, nature, or consequences of the study, or has any condition which in the Investigator's opinion would constitute an unacceptable risk to the subject's safety.
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Is receiving an investigational drug, have an investigational device in place, or have participated in an investigational drug or device study within 30 days prior to Screening.
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Have chronic renal insufficiency as defined by either a Screening creatinine value greater than 2.5 mg/dL or the requirement for dialysis.
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Does not have 3 or more of the following left ventricular disease/dysfunction risk factors:
- Body mass index at least 30 kg/m^2
- History of essential hypertension
- Diabetes mellitus (any type)
- Historical evidence of significant coronary artery disease established by any 1 of the following: history of myocardial infarction, percutaneous coronary intervention, or angiographic evidence of coronary artery disease; positive stress test with imaging; previous coronary artery bypass graft; or stable angina.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description UT-15C Treprostinil Diolamine Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID Placebo Placebo Matching placebo tablets (oral)
- Primary Outcome Measures
Name Time Method Time to First Clinical Worsening Event From randomization to approximately 4 years Clinical worsening was assessed continuously from randomization until the subject's last study visit. Clinical worsening events were defined as death (all causes), hospitalizations due to worsening pulmonary arterial hypertension (PAH), initiation of an inhaled or infused prostacyclin (PGI2) for the treatment of worsening PAH, disease progression, or unsatisfactory long-term clinical response. All clinical worsening events reported by the study sites were reviewed by the Sponsor Medical Monitors. Once a clinical worsening event occurred, it was entered in the eCRF and a narrative was submitted for review by the Sponsor's Medical Monitor within 48 hours after the event became known to the Investigator or designee. Subsequently, the narratives for subjects with the reported clinical worsening events were sent to an independent adjudication committee. The independent adjudication committee reviewed and adjudicated all clinical worsening events throughout the study.
- Secondary Outcome Measures
Name Time Method Change in 6-Minute Walk Distance From Baseline to Week 24 The intent of the 6-Minute Walk Test (6MWT) is to evaluate exercise capacity associated with carrying out activities of daily living. A baseline 6MWT was performed prior to initiation of study drug on the day of randomization. 6MWTs were conducted at Weeks 4, 8, 12, 24, and every 12 weeks thereafter. The change between Baseline and Week 24 is reported.
Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 24 From Baseline to Week 24 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 Baseline (prior to starting study drug), Week 12, Week 24, the first Continued Visit, and every other Continued Visit thereafter (ie, Continued Visits 3, 5, 7, etc). NT-proBNP was also assessed at the Study Drug Termination Visit. The change between Baseline and Week 24 is reported.
Change in World Health Organization Functional Class (WHO FC) From Baseline to Week 48 Baseline to Week 48 The WHO FC for PAH was assessed at Baseline prior to starting study drug, at all subsequent scheduled study visits, and every time the 6MWT was performed for purposes of assessing clinical worsening status.
Trial Locations
- Locations (154)
University of Arizona
🇺🇸Tucson, Arizona, United States
University of Florida College of Medicine Jacksonville
🇺🇸Jacksonville, Florida, United States
The First Affiliated Hospital of Nanjing Medical University
🇨🇳Nanjing, Jiangsu, China
Zhongshan Hospital Fudan University
🇨🇳Shanghai, Shanghai, China
CHU de Montpellier
🇫🇷Montpellier Cedex 5, Languedoc-roussillon, France
Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im K. Marcinkowskiego w Poznaniu
🇵🇱Krakow, Poland
Centre Hospitalier Régional Universitaire de Lille - Hôpital Claude Huriez
🇫🇷Lille, NORD Pas-de-calais, France
Peking Union Medical College Hospital
🇨🇳Beijing, China
Chinese PLA General Hospital
🇨🇳Beijing, China
West China Hospital
🇨🇳Chengdu, Sichuan, China
The Affiliated Hospital of Qingdao University
🇨🇳Qingdao, China
Hopital Jean Minjoz Centre Hospitalier Universitaire Besancon
🇫🇷Besancon, Franche-comte, France
Papworth Hospital
🇬🇧Papworth Everard, Cambridgshire, United Kingdom
The Second Affiliated Hospital of Nanchang Medical University
🇨🇳Nanchang, Jiangxi, China
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
🇨🇳Shanghai, Shanghai, China
Istituto Mediterraneo Trapianti e Terapia Alta Specializzazione (ISMETT)
🇮🇹Palermo, Italy
Centre Hospitalier Universitaire Hopital Nord
🇫🇷Marseille, Provence Alpes COTE D'azur, France
Universitätskrankenhaus Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Azienda Policlinico Umberto I di Roma
🇮🇹Roma, Italy
Care Institute Medical Sciences
🇮🇳Ahmedabad, Gujarat, India
Gachon University Gil Medical Center
🇰🇷Incheon, Korea, Republic of
Vrije Universiteit Medisch Centrum
🇳🇱Amsterdam, Noord-holland, Netherlands
The Ohio State University
🇺🇸Columbus, Ohio, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
University Hospital
🇺🇸Cleveland, Ohio, United States
University of California, San Francisco-Fresno
🇺🇸Fresno, California, United States
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
David Geffen School of Medicine
🇺🇸Torrance, California, United States
University of Florida
🇺🇸Gainesville, Florida, United States
University of Florida College of Medicine Jacksonville- Division of Pulmonary & Critical Medicine
🇺🇸Jacksonville, Florida, United States
University of Florida College of Medicine, Jacksonville
🇺🇸Jacksonville, Florida, United States
Cleveland Clinic Florida
🇺🇸Weston, Florida, United States
Emory University Hospital
🇺🇸Atlanta, Georgia, United States
Augusta University
🇺🇸Augusta, Georgia, United States
Piedmont - Georgia Lung Associates
🇺🇸Austell, Georgia, United States
HeartCare Midwest
🇺🇸Peoria, Illinois, United States
Indiana University Hospital
🇺🇸Carmel, Indiana, United States
University of Maryland
🇺🇸Baltimore, Maryland, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Beaumont Health
🇺🇸Troy, Michigan, United States
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
Asheville Cardiology Associates
🇺🇸Asheville, North Carolina, United States
Perelman Center for Advanced Medicine; University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Sentara Cardiovascular Research Institute
🇺🇸Norfolk, Virginia, United States
University of Pittsburgh Medical Center - Presbyterian Cardiovascular Institute
🇺🇸Pittsburgh, Pennsylvania, United States
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States
Hospital Italiano de Buenos Aires
🇦🇷Ciudad Autónoma de Buenos Aires, Distrito Federal, Argentina
Sanatorio San José
🇦🇷Caba, Buenos Aires, Argentina
Hospital Italiano Garibaldi
🇦🇷Rosario, Santa Fe, Argentina
Sanatorio de la Trinidad Mitre
🇦🇷Buenos Aires, Argentina
Hospital Dr. José María Cullen
🇦🇷Santa Fe, Argentina
Royal Prince Alfred Hospital
🇦🇺Camperdown, New South Wales, Australia
Saint Vincents Hospital
🇦🇺Sydney, New South Wales, Australia
Nepean Hospital
🇦🇺Kingswood, New South Wales, Australia
Macquarie University
🇦🇺Sydney, New South Wales, Australia
Prince Charles Hospital
🇦🇺Chermside, Queensland, Australia
Royal Hobart Hospital
🇦🇺Hobart, Tasmania, Australia
The Alfred Hospital
🇦🇺Melbourne, Victoria, Australia
Royal Melbourne Hospital
🇦🇺Parkville, Victoria, Australia
Krankenhaus Elisabethinen Linz
🇦🇹Linz, Upper Austria, Austria
Medizinische Universität Wien
🇦🇹Wien, Austria
Hospital das Clinicas da Universidade Federal de Goias
🇧🇷Goiania, Goias, Brazil
Hospital das Clínicas da Faculdade de Medicina de Botucatu- UNESP
🇧🇷Botucatu, SAO Paulo, Brazil
Hospital da Clínicas da Faculdade de Medicina da Universidade de São Paulo
🇧🇷São Paulo, SAO Paulo, Brazil
Escola Paulista de Medicina, Universidade Federal de São Paulo
🇧🇷São Paulo, SAO Paulo, Brazil
Respiratory Research Foundation
🇨🇦Calgary, Alberta, Canada
Hospital Alemão Oswaldo Cruz
🇧🇷São Paulo, Brazil
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
Vancouver Coastal Health
🇨🇦Vancouver, British Columbia, Canada
Lawson Health Research Institute
🇨🇦London, Ontario, Canada
Centro de Investigaciones TASOL
🇨🇱Santiago, Region Metropolitana, Chile
Clínica Tabancura
🇨🇱Vitacura, Santiago, Chile
Beijing Chao-Yang Hospital
🇨🇳Beijing, Beijing, China
Guangdong General Hospital
🇨🇳Guangzhou, Guangdong, China
Wuhan Asia Heart Hospital
🇨🇳Wuhan, Hubei, China
Xiangya Hospital
🇨🇳Changsha, Hunan, China
Rigshospitalet-Copenhagen University Hospital
🇩🇰Copenhagen, Denmark
Hopital Haut-Leveque, CHU Bordeaux
🇫🇷Pessac, Aquitaine, France
Hopital Brabois
🇫🇷Vandoeuvre-Les-Nancy, Limousin, Lorraine, France
Thoraxklinik am Universitätsklinikum Heidelberg
🇩🇪Heidelberg, Baden-wuerttemberg, Germany
Ludwig-Maximilians-Universitat Munchen
🇩🇪Munchen, Bayern, Germany
Universitätsklinikum Regensburg
🇩🇪Regensburg, Bayern, Germany
Missionsarztliche Klinik Wurzburg gGmbH
🇩🇪Wurzburg, Bayern, Germany
Bergmannsheil Berufsgenossenschaftliche Universitätsklinik GmbH
🇩🇪Bochum, Nordrhein-westfalen, Germany
Herzzentrum Duisburg
🇩🇪Duisburg, Nordrhein-westfalen, Germany
Universitätsklinikum Köln
🇩🇪Köln, Nordrhein-westfalen, Germany
Universitätsmedizin der Johannes Gutenberg Universität
🇩🇪Mainz, Rheinland-pfalz, Germany
Technische Universität Dresden
🇩🇪Sachsen, Germany
Universitätsklinikum Leipzig
🇩🇪Leipzig, Sachsen, Germany
University General Hospital of Attikon
🇬🇷Athens, Attica, Greece
General Hospital of Thessaloniki, "G.Papanikolaou"
🇬🇷Thessaloniki, Macedoni, Greece
Sir Ganga Ram Hospital
🇮🇳New Delhi, Delhi, India
Apollo Hospitals International, Ltd.
🇮🇳Gandhinagar, Gujarat, India
Apollo Hospital
🇮🇳Chennai, Tamil NADU, India
Rabin Medical Center
🇮🇱Petach Tikvah, Petah Tiqwa, Israel
Rambam Health Corp.
🇮🇱Haifa, Israel
Azienda Ospedaliera Universitaria
🇮🇹Napoli, Italy
Beijing Shijitan Hospital
🇨🇳Beijing, China
Renji Hospital of Shanghai Jiaotong University
🇨🇳Shanghai, China
Shanghai Pulmonary Hospital of Tongji University
🇨🇳Shanghai, China
Shenyang General Hospital of Shenyang Military Command
🇨🇳Shenyang, China
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
The University of Texas Health Science Center at Houston
🇺🇸Houston, Texas, United States
Hospital Madre Teresa
🇧🇷Belo Horizonte, Minas Gerais, Brazil
G. Kuppuswamy Naidu Memorial Hospital
🇮🇳Coimbatore, Tamil NADU, India
Complexo Hospitalar Santa Casa de Porto Alegre
🇧🇷Porto Alegre, RIO Grande DO SUL, Brazil
Hospital das Clínicas da Universidade Federal de Minas Gerais
🇧🇷Belo Horizonte, Minas Gerais, Brazil
Indraprastha Apollo Hospital
🇮🇳New Delhi, Delhi, India
University of Rochester
🇺🇸Rochester, New York, United States
Arizona Pulmonary Specialists, Ltd.
🇺🇸Phoenix, Arizona, United States
Aarhus Universitetshospital, Skejby
🇩🇰Aarhus, Denmark
Fondazione IRCCS Policlinico S. Matteo
🇮🇹Pavia, Italy
Sahlgrenska University Hospital
🇸🇪Göteborg, Vastra Gotaland, Sweden
Karolinska University Hospital Solna
🇸🇪Stockholm, Sweden
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
CARE Hospital
🇮🇳Hyderabad, Andhra Pradesh, India
Narayana Institute of Cardiac Sciences
🇮🇳Bangalore, Karnataka, India
Instituto Nacional de Cardiologia Ignacio Chavez
🇲🇽Tlalpan, Distrito Federal, Mexico
National Cheng Kung University Hospital
🇨🇳Tainan, Tainan CITY, Taiwan
Medanta - The Medicity
🇮🇳Gurgaon, Haryana, India
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Royal Free Hospital
🇬🇧London, England, United Kingdom
Universitätsmedizin Greifswald
🇩🇪Greifswald, Mecklenburg-vorpommern, Germany
Mediciti Hospital
🇮🇳Hyderabad, Andhra Pradesh, India
Uniwersytecki Szpital Kliniczny w Bialymstoku
🇵🇱Bialystok, Poland
Europejskie Centrum Zdrowia Otwock, Szpital im. Fryderyka Chopina
🇵🇱Otwock, Poland
Veterans General Hospital-Kaohsiung
🇨🇳Kaohsiung, Taiwan
Royal Hallamshire Hospital
🇬🇧Sheffield, England, United Kingdom
KEM Hospital
🇮🇳Mumbai, Maharashtra, India
Unidad de Investigacion Clinica en Medicina S.C.
🇲🇽Monterrey, Nuevo LEON, Mexico
National University Hospital
🇸🇬Singapore, Singapore
Taichung Veterans General Hospital
🇨🇳Taichung, Taiwan
The Chaim Sheba Medical Center at Tel Hashomer
🇮🇱Tel Hashomer, Tel Aviv, Israel
National Heart Centre Singapore
🇸🇬Singapore, Singapore
Universitair Medisch Centrum Sint Radboud
🇳🇱Nijmegen, Gelderland, Netherlands
Carmel Medical Center
🇮🇱Haifa, Israel
Hadassah Medical Center
🇮🇱Jerusalem, Israel
Krakowski Szpital Specjalistyczny im. Jana Pawla II
🇵🇱Malogoskie, Poland
Freeman Hospital
🇬🇧Newcastle upon Tyne, England, United Kingdom
University of California-Davis Medical Group, Advanced Lung Disease/Transplant Program
🇺🇸Sacramento, California, United States
University of Colorado Hospital
🇺🇸Aurora, Colorado, United States
Legacy Research Institute
🇺🇸Portland, Oregon, United States
Kentuckiana Pulmonary Associates
🇺🇸Louisville, Kentucky, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Aurora Saint Luke's Medical Center
🇺🇸Milwaukee, Wisconsin, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
Universitätsklinikum des Saarlandes
🇩🇪Homburg, Saarland, Germany
Ruby Hall Clinic
🇮🇳Pune, Maharashtra, India
Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States