Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)
Study Purpose
Combination therapy in pulmonary arterial hypertension (PAH) has been the subject of active investigation for more than a decade, with the benefit of targeting different pathways known to be involved in the pathogenesis of the disease. Adherence to prescribed therapy has an impact on clinical outcomes. Reducing the pill/tablet count and frequency has a major impact on patients' adherence to therapies and therefore the observed clinical outcomes. One way to simplify treatment is to use fixed-dose combination (FDC) products that combine multiple treatments targeting different pathways into a single tablet. This study aims to demonstrate that the FDC of macitentan and tadalafil is more effective than therapy with 10 mg of macitentan alone or 40 mg of tadalafil alone. This phase 3 study will evaluate the efficacy and safety at 16 weeks of an FDC (macitentan 10 mg and tadalafil 40 mg) against these two PAH-approved therapies given as monotherapy to further confirm the added value of the FDC.
Recruitment Criteria
|
Accepts Healthy Volunteers
Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms |
No |
|
Study Type
An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies. |
Interventional |
| Eligible Ages | 18 Years and Over |
| Gender | All |
Inclusion Criteria:
- - Signed and dated informed consent form (ICF) - Confirmed diagnosis of symptomatic PAH in WHO FC II or III.
- - Symptomatic PAH belonging to one of the following subgroups of WHO Group 1 pulmonary hypertension: - Idiopathic.
- - Heritable.
- - Drug- or toxin-induced.
- - Associated with connective tissue disease, HIV infection, portal hypertension or congenital heart disease with simple systemic-to-pulmonary shunt with persistent pulmonary hypertension documented by a right heart catheterization (RHC) ≥ 1 year after surgical repair.
- - PAH diagnosis confirmed by hemodynamic evaluation at rest (through central reading), evaluated within 5 weeks prior to randomization: - Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, AND.
- - Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg, AND.
- - Pulmonary vascular resistance (PVR) ≥ 3 WU (i.e., ≥ 240 dyn∙sec∙cm-5) - Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH.
- - Currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 months prior to baseline RHC, within the prespecified doses in the study protocol or no history of PAH-specific treatment.
- - Participant able to perform the 6MWT with a minimum distance of 100 m and maximum distance of 450 m at Screening.
- - A woman of childbearing potential must: - have negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization.
- - agree to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation.
- - agree to follow the contraception scheme from Screening up to at least 30 days after study treatment discontinuation.
Exclusion Criteria:
- - Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form of prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused routes) in the 3-month period prior to start of treatment.
- - Treatment with combination therapy of ERA and PDE-5i in the 3-month period prior to start of treatment or history of intolerance to ERA and PDE-5i combination therapy.
- - Hypersensitivity to any of the study treatments or any excipient of their formulations.
- - Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer in the 1-month period prior to start of treatment.
- - Treatment with a strong CYP3A4 inhibitor or a moderate dual CYP3A4/CYP2C9 inhibitor or co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors in the 1-month period prior to start of treatment.
- - Treatment with doxazosin.
- - Treatment with any form of organic nitrate, either regularly or intermittently.
- - Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start of treatment.
- - Treatment with another investigational drug in the 3-month period prior to start of treatment.
- - Body mass index (BMI) > 40 kg/m2 at Screening.
- - Known presence of three or more of the following risk factors for heart failure with preserved ejection fraction at Screening: - BMI > 30 kg/m2.
- - Diabetes mellitus of any type.
- - Essential hypertension (even if well controlled) - Coronary artery disease, i.e. history of stable angina or known more than 50% stenosis in a coronary artery or history of myocardial infarction or history of or planned coronary artery bypass grafting and/or coronary artery stenting.
- - Known presence of moderate or severe obstructive lung disease any time prior to Screening as specified in study protocol.
- - Known presence of moderate or severe restrictive lung disease any time prior to Screening as specified in study protocol.
- - Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive left-sided cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction; or left ventricular outflow obstruction, in the opinion of the investigator.
- - Known permanent atrial fibrillation, in the opinion of the investigator.
- - Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism) - Documented pulmonary veno-occlusive disease.
- - Hemoglobin < 100 g/L (<10 g/dL) at Screening.
- - Known severe hepatic impairment as specified in study protocol.
- - Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 × upper limit of normal (ULN) at Screening.
- - Severe renal impairment at Screening as specified in study protocol.
- - Systemic hypotension at Screening or Randomization and systemic hypertension at Screening as specified in study protocol.
- - Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last 26 weeks prior to Screening.
- - Known bleeding disorder, in the opinion of the investigator.
- - Loss of vision in one or both eyes because of non-arteritic anterior ischemic optic neuropathy.
- - Hereditary degenerative retinal disorders, including retinitis pigmentosa.
- - History of priapism, conditions that predispose to priapism (example, sickle cell anemia, multiple myeloma, or leukemia) or anatomical deformation of the penis (example, angulation, cavernosal fibrosis, or Peyronie's disease) - Difficulty swallowing large pills/tablets that would interfere with the ability to comply with study treatment regimen.
- - Any planned surgical intervention (including organ transplant) during the double-blind treatment period, except minor interventions.
- - Exercise training program for cardiopulmonary rehabilitation in the 12-week period prior to start of treatment, or planned to be started during the double-blind period of the study.
- - Pregnant, planning to become pregnant or lactating.
- - Any known factor or disease that might interfere with treatment adherence, full participation in the study or interpretation of the results as judged by the investigator (e.g., drug or alcohol dependence etc.) - Known concomitant life-threatening disease with a life expectancy less than (<) 12 months.
Trial Details
|
Trial ID:
This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries. |
NCT03904693 |
|
Phase
Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use. |
Phase 3 |
|
Lead Sponsor
The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data. |
Actelion |
|
Principal Investigator
The person who is responsible for the scientific and technical direction of the entire clinical study. |
Hany Rofael, MD |
| Principal Investigator Affiliation | Janssen, LP |
|
Agency Class
Category of organization(s) involved as sponsor (and collaborator) supporting the trial. |
Industry |
| Overall Status | Active, not recruiting |
| Countries | Australia, Brazil, Bulgaria, Canada, China, Czechia, Germany, Hungary, Italy, Japan, Malaysia, Mexico, Poland, Russian Federation, South Africa, Spain, Taiwan, Turkey, United States |
|
Conditions
The disease, disorder, syndrome, illness, or injury that is being studied. |
Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH) |
PAH is characterized by a progressive increase in pulmonary arterial pressure (PAP) and in pulmonary vascular resistance (PVR) potentially leading to right heart failure and death. Current PAH-specific therapeutic options include treatments that target the three pathways (endothelin, nitric oxide, and prostacyclin pathways). While combination treatment is common, FDC pills or tablets that combine two or more PAH-specific therapies are not available, thereby requiring participants to take multiple pills/tablets daily. An FDC is an attractive option for PAH participants because it simplifies the treatment regimen by combining two therapies (which would otherwise involve a total of three tablets: one macitentan 10 mg tablet and two tadalafil 20 mg tablets) into a single tablet. Macitentan is an orally active, non-peptide, potent dual endothelin receptor A and B antagonist. Tadalafil is a selective inhibitor of phosphodiesterase type-5 (PDE-5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). This study comprises the following consecutive periods: Screening period (lasts up to 30 days), Double-blind treatment period (consists of the titration phase [the first 2 weeks] and the maintenance phase [Week 3 through Week 16]), Open-label treatment period, End-of-Treatment (EOT), Safety follow-up (S-FU) period, and End of Study (EOS). The total study duration for a participant will be up to 30 months. Study assessments like physical examinations, vital signs, right heart catheterization, 6-minute walk test will be performed. Safety will be assessed throughout the study.
Arms
Experimental: FDC therapy + Placebo macitentan + Placebo tadalafil
Subjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments.
Active Comparator: Macitentan mono-therapy + Placebo tadalafil + Placebo FDC
Subjects to receive macitentan 10 mg plus matching placebos for the two other study treatments.
Active Comparator: Tadalafil mono-therapy + Placebo macitentan + Placebo FDC
Subjects to receive tadalafil 40 mg (2 x 20 mg) plus matching placebos for the two other study treatments.
Interventions
Drug: - FDC macitentan/tadalafil
Film-coated tablet with 10 mg macitentan and 40 mg tadalafil, to be administered orally once daily.
Drug: - Macitentan 10 mg
Film-coated tablet with 10 mg macitentan, to be administered orally once daily.
Drug: - Tadalafil 40 mg
Film-coated tablet with 40 mg tadalafil (2 x 20 mg tablets), to be administered orally once daily.
Drug: - Placebo FDC
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
Drug: - Placebo macitentan
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
Drug: - Placebo tadalafil
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
Contact a Trial Team
If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.
Status
Address
Providence Medical Foundation
Fullerton, California, 92835
Status
Address
University of Southern California
Los Angeles, California, 90033
Status
Address
Piedmont Healthcare
Atlanta, Georgia, 30309
Status
Address
WellStar Health System
Marietta, Georgia, 30060
Status
Address
OSF HealthCare Cardiovascular Institute
Peoria, Illinois, 61614
Status
Address
University of Iowa Hospitals & Clinics
Iowa City, Iowa, 52242
Status
Address
Norton Healthcare
Louisville, Kentucky, 40202-1332
Status
Address
Sparrow Clinical Research Institute
Lansing, Michigan, 48912
Status
Address
Minneapolis Heart Institute Foundation
Minneapolis, Minnesota, 55407
Status
Address
Washington University School of Medicine
Saint Louis, Missouri, 63110
Status
Address
VA Sierra Nevada Health Care System
Reno, Nevada, 89509
Status
Address
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27514
Status
Address
Pitt County Memorial Hospital d/b/a Vidant Medical Center
Greenville, North Carolina, 27835
Status
Address
Sanford Health
Fargo, North Dakota, 58122
Status
Address
University of Cincinnati
Cincinnati, Ohio, 45267
Status
Address
St. Elizabeth Hospital Mercy Bon Secors
Youngstown, Ohio, 44503
Status
Address
Legacy Hospital
Portland, Oregon, 97210
Status
Address
Oregon Health and Science University
Portland, Oregon, 97239
Status
Address
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, 19107
Status
Address
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, 15213
Status
Address
Sanford Health
Sioux Falls, South Dakota, 57105
Status
Address
University of Texas Southwestern Medical Center
Dallas, Texas, 75390
Status
Address
Baylor Scott White - Plano
Plano, Texas, 75093
Status
Address
WVU Health Sciences Center
Morgantown, West Virginia, 26506
Status
Address
University of Wisconsin At Madison
Madison, Wisconsin, 53792
Status
Address
Medical College of Wisconsin Froedtert Hospital
Milwaukee, Wisconsin, 53226
International Sites
Status
Address
Royal Adelaide Hospital
Adelaide, , 5000
Status
Address
Pulmonary Arterial Hypertension Clinic
Hobart, , 7000
Status
Address
Core Research Group
Milton, , 4064
Status
Address
Universidade Federal De Minas Gerais - Hospital das Clínicas
Belo Horizonte, , 30130-100
Status
Address
Instituto das Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa
Belo Horizonte, , 30441-070
Status
Address
Fundacao para o Desenvolvimento Medico Hospitalar (UNESP Botucatu)
Botucatu, , 18618-686
Status
Address
Secretaria da Saude do Estado do Ceara - Hospital Doutor Carlos Alberto Studart Gomes
Fortaleza, , 60840-285
Status
Address
Universidade Federal de Goias - Hospital das Clinicas da UFG
Goiania, , 74605-020
Status
Address
Hospital das Clinicas de Porto Alegre
Porto Alegre, , 90035-007
Status
Address
Irmandade Santa Casa de Misericordia de Porto Alegre
Porto Alegre, , 90035-074
Status
Address
Uniao Brasileira de Educaçao e Assistencia-Hospital Sao Lucas da PUCRS
Porto Alegre, , 90610-000
Status
Address
Hospital Das Clinicas Da Faculdade De Medicina Da USP
Sao Paulo, , 05403-000
Status
Address
SPDM - Associacao Paulista para o Desenvolvimento da Medicina - Hospital Sao Paulo
São Paulo, , 04024-002
Status
Address
National Heart Hospital
Sofia, , 1309
Status
Address
University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD
Sofia, , 1750
Status
Address
Alberta Health Services
Calgary, Alberta, T1Y 6J4
Status
Address
University of Alberta
Edmonton, Alberta, T6G 2G3
Status
Address
Vancouver General Hospital
Vancouver, British Columbia, V5Z 1M9
Status
Address
London Health Sciences Centre
London, Ontario, N6A 5W9
Status
Address
Beijing Anzhen Hospital
Beijing, , 100029
Status
Address
The Second Xiangya Hospital of Central South Hospital
Changsha, , 410011
Status
Address
The First Affiliated Hospital of Guangzhou Medical University
Guangzhou, , 510120
Status
Address
Jiangsu Province Hospital
Nanjing, ,
Status
Address
Shanghai Pulmonary Hospital
Shanghai, , 200433
Status
Address
The General Hospital of Northern Theater Command
Shenyang, , 110000
Status
Address
Tianjin Medical University General Hospital
Tian Jin, , 300052
Status
Address
The First Affiliated Hospital of Xian Jiaotong University
Xi'An, , 710061
Status
Address
General University Hospital II.department of Internal Medicine-cardiology and angiology
Praha 2, , 128 08
Status
Address
Universitatsklinikum Bonn
Bonn, , 53105
Status
Address
Universitatsklinikum Carl Gustav Carus Dresden
Dresden, , 01307
Status
Address
Universitaetsklinikum Giessen
Giessen, , 35392
Status
Address
Universitat Greifswald
Greifswald, , 17475
Status
Address
Universitaetsklinikum Hamburg Eppendorf
Hamburg, , 20246
Status
Address
Thoraxklinik am Universitätsklinikum Heidelberg
Heidelberg, , 69126
Status
Address
Kardiologische Praxis Papenburg
Papenburg, , 26871
Status
Address
Universitaetsklinikum Regensburg
Regensburg, , 93053
Status
Address
Klinikum Würzburg Mitte gGmbH Standort Missioklinik
Würzburg, , 97074
Status
Address
Semmelweis Egyetem,Pulmonológiai Klinika
Budapest, , 1083
Status
Address
Gottsegen György Országos Kardiológiai Intézet, Felnőtt kardiológiai osztály
Budapest, , 1096
Status
Address
Pecsi Tudomanyegyetem Klinikai Kozpont
Pecs, , 7624
Status
Address
Szegedi Tudomanyegyetem
Szeged, , 6725
Status
Address
Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari
Bari, , 70124
Status
Address
Cardiologia c/o Spedali Civili
Brescia, , 25123
Status
Address
Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
Milano, , 20122
Status
Address
Azienda Ospedaliera San Gerardo
Monza, , 20090
Status
Address
Ospedale San Francesco
Nuoro, , 08100
Status
Address
IRCCS Policlinico San Matteo, Università degli studi di Pavi
Pavia, , 27100
Status
Address
Policlinico Umberto I
Roma, , 00161
Status
Address
The University of Tokyo Hospital
Bunkyo, , 113-8655
Status
Address
Chiba University Hospital
Chiba, , 260 8677
Status
Address
Kyushu University Hospital
Fukuoka, , 812-8582
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Address
Fukushima Medical University Hospital
Fukushima, , 960-1295
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Address
Gunma University Hospital
Gunma, , 371-0034
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Address
Kure Kyosai Hospital
Hiroshima, , 737-8505
Status
Address
Tokai University Hospital
Isehara, , 259-1193
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Address
Kagoshima University Hospital
Kagoshima City, , 890-8544
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Address
Kanazawa University Hospital
Kanazawa, , 920-8641
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Address
Kobe University Hospital
Kobe, , 650-0017
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Address
Kumamoto University Hospital
Kumamoto-City, , 860-8556
Status
Address
Kurume University Hospital
Kurume, , 830-0011
Status
Address
University Hospital Kyoto Perfectural University of Medicine
Kyoto, , 602-8566
Status
Address
Kyoto University Hospital
Kyoto, , 606-8507
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Address
Shinshu University Hospital
Matsumoto, , 390-8621
Status
Address
Kyorin University Hospital
Mitaka, , 181-8611
Status
Address
Nagasaki University Hospital
Nagasaki-shi, , 852-8501
Status
Address
Okayama University Hospital
Okayama, , 700-8558
Status
Address
National Hospital Organization Okayama Medical Center
Okayama, , 701-1192
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Address
Hokkaido University Hospital
Sapporo-shi, , 060-8648
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Address
Sapporo Medical University Hospital
Sapporo, , 060-8543
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Address
Tohoku University Hospital
Sendai, , 980-8574
Status
Address
National Cerebral and Cardiovascular Center
Suita-Shi, , 564-8565
Status
Address
Juntendo University Hospital
Tokyo, , 113-8431
Status
Address
University of Tsukuba Hospital
Tsukuba-City, , 305-8576
Status
Address
Mie University Hospital
Tsu, , 514 8507
Status
Address
Institut Jantung Negara (National Heart Institute)
Kuala Lumpur, , 50400
Status
Address
Sarawak Heart Center
Kuching, , 94300
Status
Address
Instituto Nacional de Cardiologia Dr. Ignacio Chavez
Mexico, , 14080
Status
Address
Unidad de Investigacion Clinica en Medicina S.C. (UDICEM)
Monterrey, , 64718
Status
Address
Klinika Kardiologii z Oddzialem Intensywnego Nadzoru Kardiologicznego, UM w Białymstoku
Białystok, , 15-276
Status
Address
Szpital Uniwersytecki nr 2 im dr Jana Biziela w Bydgoszczy, Klinika Kardiologii
Bydgoszcz, , 85-168
Status
Address
Uniwersyteckie Centrum Kliniczne
Gdansk, , 80-214
Status
Address
GCM SUM, I Oddzial Kardiologii
Katowice, , 40-635
Status
Address
Oddzial Kardiologii Wojewodzki Szpital Specjalistyczny im. W.Bieganskiego
Lodz, , 91-347
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Address
Wojewodzki Szpital Specjalistyczny im. Stefana Kardynala Wyszynskiego SPZOZ, Oddzial Kardiologii
Lublin, , 20-718
Status
Address
ECZ Otwock Klinika Kardiologii, Klinika Krążenia Płucnego Chorób Zakrzepowo-Zatorowych i Kardiologii
Otwock, , 05-400
Status
Address
SPSK2 PUM, Klinika Kardiologii
Szczecin, , 70-111
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Address
Wojewodzki Szpital Specjalistyczny, Oddzial Kardiologiczny
Wrocław, , 51-124
Status
Address
Altay Regional Cardiological Dispensary
Barnaul, , 656055
Status
Address
Scientific and Research Institution of Cardiovascular Diseases Complex Problems
Kemerovo, , 650002
Status
Address
National Medical Research Center of Cardiology of MoH of Russian Federation
Moscow, , 121552
Status
Address
GU Moscow Regional Research Clinical Institute n.a. M.F.Vla
Moscva, , 129090
Status
Address
National medical Research Center n.a. V.A.Almazov of MoH of Russian Federation
Saint-Petersburg, , 197341
Status
Address
Samara Regional Clinical Cardiological Dispensary
Samara, , 443070
Status
Address
Abdullah, IA
Durban, , 4001
Status
Address
Dr Kalla
Lenasia, , 1820
Status
Address
Hosp. Clinic de Barcelona
Barcelona, , 08036
Status
Address
Hosp. Univ. Vall D Hebron
Barcelona, , 8035
Status
Address
Hosp. Univ. Ramon Y Cajal
Madrid, , 28034
Status
Address
Hosp. Univ. Fund. Jimenez Diaz
Madrid, , 28040
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Address
Hosp. Univ. La Paz
Madrid, , 28046
Status
Address
Hosp. Clinico Univ. de Salamanca
Salamanca, , 37007
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Address
Hosp. Univ. Marques de Valdecilla
Santander, , 39011
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Address
Hosp. Virgen de La Salud
Toledo, , 45004
Status
Address
Hosp. Gral. Univ. Valencia
Valencia, , 46014
Status
Address
Kaohsiung Veterans General Hospital
Kaohsiung, , 813
Status
Address
National Cheng Kung University Hospital
Tainan, , 704
Status
Address
National Taiwan University Hospital
Taipei, , 10002
Status
Address
Mackay Memorial Hospital
Taipei, , 10449
Status
Address
Taipei Veterans General Hospital
Taipei, , 112
Status
Address
Chang-Gung Memorial Hospital, LinKou Branch
Taoyuan, , 333
Status
Address
Cukurova University Medical Faculty
Adana, , 01790
Status
Address
Hacettepe University Medical Faculty
Ankara, , 6100
Status
Address
Ankara University Medical Faculty
Ankara, , 6500
Status
Address
Bursa Yuksek Ihtisas Training and Research Hospital
Bursa, , 16310
Status
Address
Istanbul University - Cerrahpasa Cardiology Institution
Istanbul, , 34096
Status
Address
Istanbul University Cerrahpasa Medical Faculty
Istanbul, , 34096
Status
Address
Marmara University Medical Faculty
Istanbul, , 34899
Status
Address
Ege University School of Medicine
Izmir, , 35100
Status
Address
Dokuz Eylul University Hospital
Izmir, , 35340
Status
Address
Kartal Kosuyolu Yuksek Ihtisas Egitim Ve Arastirma Hastanesi
Kartal Istanbul, , 34865
Status
Address
Konya Selcuk University Medical Faculty
Konya, , 42131
Status
Address
Mersin University Medical Faculty
Mersin, , 33110
