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出境医 / 临床实验 / Sphingosine-1-phosphate and Pneumonia (SOPN)

Sphingosine-1-phosphate and Pneumonia (SOPN)

Study Description
Brief Summary:
Pneumonia is a major infectious cause of death worldwide and imposes a considerable burden on healthcare resources. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid and involved in many physiological processes including immune responses and endothelial barrier integrity. In term of endothelial barrier integrity, S1P plays a crucial role in protecting lungs from pulmonary leak and lung injury. Because of the involvement in lung injury, S1P could be the potential biomarker of pneumonia. Recently, our pilot study suggested that patients with CAP have significantly higher plasma S1P levels than healthy individuals. Interestingly, our observational study also showed significantly elevated S1P level in the patients who were treated with methylprednisolone during the hospitalization. Based on the above evidence, we hypothesize that S1P plays an important role in the pathobiology of pneumonia. Moreover, S1P is not only a useful biomarker for diagnosis of CAP, but also can be an indicator for using corticosteroids adjuvant therapy.

Condition or disease Intervention/treatment Phase
Pneumonia, Bacterial Drug: Methylprednisolone Sodium Succinate Drug: Placebo Phase 2 Phase 3

Detailed Description:

Lower respiratory tract infections are the most frequent infectious cause of death worldwide[1] and impose a considerable burden on healthcare resources. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid and has both extracellular and intracellular effects in mammalian cells[2-5]. S1P is involved in many physiological processes including immune responses and endothelial barrier integrity[6-9]. In the context of endothelial barrier integrity, S1P plays a crucial role in protecting the lungs from the pulmonary leak and lung injury. [10-13] Previous research suggests that, at low concentrations, S1P signaling through S1PR1 is crucial for enhancing endothelial barrier function. [13,14] The S1P induces actin polymerization and results in the spreading of endothelial cells, which fill the intercellular gaps. Also, the S1P signaling can stabilize the endothelial cell-cell junctions, such as adherens junction and tight junction. [15-17] Both actin-dependent outward spreading of endothelial cells and cell junction stabilization enhance the endothelial barrier function. However, S1P at higher concentration (> 5 µM) causes endothelial barrier disruption through binding of S1PR2[13]. Thus, exact maintenance of physiologic S1P concentrations and homeostasis of S1PRs and S1P synthesis and degradation seem to be crucial for the preservation of lung endothelial barrier integrity, particularly in inflammatory lung diseases.

Because of the involvement in lung injury and endothelial barrier function, S1P may be a potential biomarker of pneumonia. Moreover, a recent study proposed that targeting the S1P/S1P receptor 2-signaling pathway in the lung may provide a novel therapeutic perspective in pneumonia for the prevention of acute lung injury [18]. Recently, our pilot study suggests that the patients with CAP (N= 137) have significantly higher plasma S1P levels than controls (N= 78). Further, the S1P levels, but not CRP, were found to be inversely correlated with PSI score, CURB-65 score and hospital length of stay (LOS) in patients with CAP. Our initial findings suggest that plasma S1P is a potential biomarker for predicting prognosis in CAP.

Although corticosteroids adjuvant therapy for CAP is still controversial, a recent meta-analysis study showed that corticosteroids adjuvant therapy in patients with the severe CAP could reduce the rate of in-hospital mortality and reduce the length of hospital stay[19]. Recently, the long-standing dogma of cytokine repression by the glucocorticoid was challenged. Vettorazzi et al. proposed a new mechanism of glucocorticoid action. They suggested that increased circulating sphingosine 1-phosphate levels resulting from the induction of sphingosine kinase 1 (SphK1) by glucocorticoids were essential for the inhibition of pulmonary inflammation[20]. Interestingly, our observational study also showed significantly elevated S1P levels in patients who were treated with methylprednisolone during hospitalization.

Several studies have suggested that S1P can enhance pulmonary endothelial cell barrier function, suggesting that higher S1P levels could be potentially beneficial. Hence, the patients, who are unable to produce sufficient S1P, might have a poor prognosis. However, in most of the studies, CAP was not considered as a disease model, and those results were based on cell lines and mouse models. Therefore, further clinical studies focusing on the role of S1P in the pathophysiology of pneumonia is needed.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Official Title: To Assess the Role of Sphingosine-1-phosphate in the Pathobiology of Pneumonia: Generate a New Strategy for Treatment of Severe Community-acquired Pneumonia
Actual Study Start Date : June 15, 2019
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : November 2025
Arms and Interventions
Arm Intervention/treatment
Experimental: methylprednisolone
20 mg of methylprednisolone IV Q12H for 5 days
 Drug: Methylprednisolone Sodium Succinate
methylprednisolone vial
Placebo Comparator: Placebo
normal saline IV Q12H for 5 days
 Drug: Placebo
Normal saline manufactured to mimic methylprednisolone vial
Outcome Measures
Primary Outcome Measures :
  1. Mortality [ Time Frame: up to 4 months ]
    In hospital mortality


Secondary Outcome Measures :
  1. ICU Admission [ Time Frame: up to 4 months ]
    If the patient has any Intensive Care Unit (ICU) Admission?

  2. Length of ICU stay [ Time Frame: up to 4 months ]
    Length of ICU stay (day)

  3. length of hospital stay [ Time Frame: up to 4 months ]
    length of hospital stay (day)


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Clinical symptoms suggestive community-acquired pneumonia and pneumonia severe index (PSI) > 90, Age 18 years or older and Written informed consent obtained

Exclusion Criteria:

  • Presence of severe immunosuppression (HIV infection, use of immunosuppressants), malignancy, pregnancy or breastfeeding, patient with uncontrol diabetes, current use of antibiotics or corticosteroids, any likely infection other than CAP, or pneumonia that developed within 3 days after hospital discharge
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Shih-Chang Hsu, MD 0982770936 1980bradhsu@gmail.com

Locations
Layout table for location information
Taiwan
Wan Fang Hospital Recruiting
Taipei City, Taiwan, 11696
Contact: Shih-Chang Hsu, MD    982770936    1980bradhsu@gmail.com   
Sponsors and Collaborators
Taipei Medical University WanFang Hospital
Investigators
Layout table for investigator information
Principal Investigator: Ching-Wang Hsu, MD Wan Fang Hospital
Tracking Information
First Submitted Date  ICMJE April 23, 2019
First Posted Date  ICMJE July 5, 2019
Last Update Posted Date July 5, 2019
Actual Study Start Date  ICMJE June 15, 2019
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 2, 2019) 		Mortality [ Time Frame: up to 4 months ]
In hospital mortality
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: July 2, 2019)
  • ICU Admission [ Time Frame: up to 4 months ]
    If the patient has any Intensive Care Unit (ICU) Admission?
  • Length of ICU stay [ Time Frame: up to 4 months ]
    Length of ICU stay (day)
  • length of hospital stay [ Time Frame: up to 4 months ]
    length of hospital stay (day)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Sphingosine-1-phosphate and Pneumonia
Official Title  ICMJE To Assess the Role of Sphingosine-1-phosphate in the Pathobiology of Pneumonia: Generate a New Strategy for Treatment of Severe Community-acquired Pneumonia
Brief Summary Pneumonia is a major infectious cause of death worldwide and imposes a considerable burden on healthcare resources. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid and involved in many physiological processes including immune responses and endothelial barrier integrity. In term of endothelial barrier integrity, S1P plays a crucial role in protecting lungs from pulmonary leak and lung injury. Because of the involvement in lung injury, S1P could be the potential biomarker of pneumonia. Recently, our pilot study suggested that patients with CAP have significantly higher plasma S1P levels than healthy individuals. Interestingly, our observational study also showed significantly elevated S1P level in the patients who were treated with methylprednisolone during the hospitalization. Based on the above evidence, we hypothesize that S1P plays an important role in the pathobiology of pneumonia. Moreover, S1P is not only a useful biomarker for diagnosis of CAP, but also can be an indicator for using corticosteroids adjuvant therapy.
Detailed Description

Lower respiratory tract infections are the most frequent infectious cause of death worldwide[1] and impose a considerable burden on healthcare resources. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid and has both extracellular and intracellular effects in mammalian cells[2-5]. S1P is involved in many physiological processes including immune responses and endothelial barrier integrity[6-9]. In the context of endothelial barrier integrity, S1P plays a crucial role in protecting the lungs from the pulmonary leak and lung injury. [10-13] Previous research suggests that, at low concentrations, S1P signaling through S1PR1 is crucial for enhancing endothelial barrier function. [13,14] The S1P induces actin polymerization and results in the spreading of endothelial cells, which fill the intercellular gaps. Also, the S1P signaling can stabilize the endothelial cell-cell junctions, such as adherens junction and tight junction. [15-17] Both actin-dependent outward spreading of endothelial cells and cell junction stabilization enhance the endothelial barrier function. However, S1P at higher concentration (> 5 µM) causes endothelial barrier disruption through binding of S1PR2[13]. Thus, exact maintenance of physiologic S1P concentrations and homeostasis of S1PRs and S1P synthesis and degradation seem to be crucial for the preservation of lung endothelial barrier integrity, particularly in inflammatory lung diseases.

Because of the involvement in lung injury and endothelial barrier function, S1P may be a potential biomarker of pneumonia. Moreover, a recent study proposed that targeting the S1P/S1P receptor 2-signaling pathway in the lung may provide a novel therapeutic perspective in pneumonia for the prevention of acute lung injury [18]. Recently, our pilot study suggests that the patients with CAP (N= 137) have significantly higher plasma S1P levels than controls (N= 78). Further, the S1P levels, but not CRP, were found to be inversely correlated with PSI score, CURB-65 score and hospital length of stay (LOS) in patients with CAP. Our initial findings suggest that plasma S1P is a potential biomarker for predicting prognosis in CAP.

Although corticosteroids adjuvant therapy for CAP is still controversial, a recent meta-analysis study showed that corticosteroids adjuvant therapy in patients with the severe CAP could reduce the rate of in-hospital mortality and reduce the length of hospital stay[19]. Recently, the long-standing dogma of cytokine repression by the glucocorticoid was challenged. Vettorazzi et al. proposed a new mechanism of glucocorticoid action. They suggested that increased circulating sphingosine 1-phosphate levels resulting from the induction of sphingosine kinase 1 (SphK1) by glucocorticoids were essential for the inhibition of pulmonary inflammation[20]. Interestingly, our observational study also showed significantly elevated S1P levels in patients who were treated with methylprednisolone during hospitalization.

Several studies have suggested that S1P can enhance pulmonary endothelial cell barrier function, suggesting that higher S1P levels could be potentially beneficial. Hence, the patients, who are unable to produce sufficient S1P, might have a poor prognosis. However, in most of the studies, CAP was not considered as a disease model, and those results were based on cell lines and mouse models. Therefore, further clinical studies focusing on the role of S1P in the pathophysiology of pneumonia is needed.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Condition  ICMJE Pneumonia, Bacterial
Intervention  ICMJE
  • Drug: Methylprednisolone Sodium Succinate
    methylprednisolone vial
  • Drug: Placebo
    Normal saline manufactured to mimic methylprednisolone vial
Study Arms  ICMJE
  • Experimental: methylprednisolone
    20 mg of methylprednisolone IV Q12H for 5 days
    Intervention: Drug: Methylprednisolone Sodium Succinate
  • Placebo Comparator: Placebo
    normal saline IV Q12H for 5 days
    Intervention: Drug: Placebo
Publications *
  • Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O'Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, Phillips D, Pierce K, Pope CA 3rd, Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De León FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012 Dec 15;380(9859):2095-128. doi: 10.1016/S0140-6736(12)61728-0. Erratum in: Lancet. 2013 Feb 23;381(9867):628. AlMazroa, Mohammad A [added]; Memish, Ziad A [added].
  • Rosen H, Goetzl EJ. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol. 2005 Jul;5(7):560-70. Review.
  • Anliker B, Chun J. Cell surface receptors in lysophospholipid signaling. Semin Cell Dev Biol. 2004 Oct;15(5):457-65. Review.
  • Meyer zu Heringdorf D, Liliom K, Schaefer M, Danneberg K, Jaggar JH, Tigyi G, Jakobs KH. Photolysis of intracellular caged sphingosine-1-phosphate causes Ca2+ mobilization independently of G-protein-coupled receptors. FEBS Lett. 2003 Nov 20;554(3):443-9.
  • Usatyuk PV, He D, Bindokas V, Gorshkova IA, Berdyshev EV, Garcia JG, Natarajan V. Photolysis of caged sphingosine-1-phosphate induces barrier enhancement and intracellular activation of lung endothelial cell signaling pathways. Am J Physiol Lung Cell Mol Physiol. 2011 Jun;300(6):L840-50. doi: 10.1152/ajplung.00404.2010. Epub 2011 Apr 8.
  • Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y, Camerer E, Zheng YW, Huang Y, Cyster JG, Coughlin SR. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science. 2007 Apr 13;316(5822):295-8. Epub 2007 Mar 15.
  • Rivera J, Proia RL, Olivera A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol. 2008 Oct;8(10):753-63. doi: 10.1038/nri2400. Review.
  • Schuchardt M, Tölle M, Prüfer J, van der Giet M. Pharmacological relevance and potential of sphingosine 1-phosphate in the vascular system. Br J Pharmacol. 2011 Jul;163(6):1140-62. doi: 10.1111/j.1476-5381.2011.01260.x. Review.
  • Xiong Y, Hla T. S1P control of endothelial integrity. Curr Top Microbiol Immunol. 2014;378:85-105. doi: 10.1007/978-3-319-05879-5_4. Review.
  • Dudek SM, Jacobson JR, Chiang ET, Birukov KG, Wang P, Zhan X, Garcia JG. Pulmonary endothelial cell barrier enhancement by sphingosine 1-phosphate: roles for cortactin and myosin light chain kinase. J Biol Chem. 2004 Jun 4;279(23):24692-700. Epub 2004 Mar 31.
  • McVerry BJ, Peng X, Hassoun PM, Sammani S, Simon BA, Garcia JG. Sphingosine 1-phosphate reduces vascular leak in murine and canine models of acute lung injury. Am J Respir Crit Care Med. 2004 Nov 1;170(9):987-93. Epub 2004 Jul 28.
  • Peng X, Hassoun PM, Sammani S, McVerry BJ, Burne MJ, Rabb H, Pearse D, Tuder RM, Garcia JG. Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury. Am J Respir Crit Care Med. 2004 Jun 1;169(11):1245-51. Epub 2004 Mar 12.
  • Sammani S, Moreno-Vinasco L, Mirzapoiazova T, Singleton PA, Chiang ET, Evenoski CL, Wang T, Mathew B, Husain A, Moitra J, Sun X, Nunez L, Jacobson JR, Dudek SM, Natarajan V, Garcia JG. Differential effects of sphingosine 1-phosphate receptors on airway and vascular barrier function in the murine lung. Am J Respir Cell Mol Biol. 2010 Oct;43(4):394-402. doi: 10.1165/rcmb.2009-0223OC. Epub 2009 Sep 11.
  • Li X, Stankovic M, Bonder CS, Hahn CN, Parsons M, Pitson SM, Xia P, Proia RL, Vadas MA, Gamble JR. Basal and angiopoietin-1-mediated endothelial permeability is regulated by sphingosine kinase-1. Blood. 2008 Apr 1;111(7):3489-97. doi: 10.1182/blood-2007-05-092148. Epub 2008 Jan 16.
  • Camerer E, Regard JB, Cornelissen I, Srinivasan Y, Duong DN, Palmer D, Pham TH, Wong JS, Pappu R, Coughlin SR. Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice. J Clin Invest. 2009 Jul;119(7):1871-9.
  • Xu M, Waters CL, Hu C, Wysolmerski RB, Vincent PA, Minnear FL. Sphingosine 1-phosphate rapidly increases endothelial barrier function independently of VE-cadherin but requires cell spreading and Rho kinase. Am J Physiol Cell Physiol. 2007 Oct;293(4):C1309-18. Epub 2007 Aug 1.
  • Arce FT, Whitlock JL, Birukova AA, Birukov KG, Arnsdorf MF, Lal R, Garcia JG, Dudek SM. Regulation of the micromechanical properties of pulmonary endothelium by S1P and thrombin: role of cortactin. Biophys J. 2008 Jul;95(2):886-94. doi: 10.1529/biophysj.107.127167. Epub 2008 Apr 11.
  • Gutbier B, Schönrock SM, Ehrler C, Haberberger R, Dietert K, Gruber AD, Kummer W, Michalick L, Kuebler WM, Hocke AC, Szymanski K, Letsiou E, Lüth A, Schumacher F, Kleuser B, Mitchell TJ, Bertrams W, Schmeck B, Treue D, Klauschen F, Bauer TT, Tönnies M, Weissmann N, Hippenstiel S, Suttorp N, Witzenrath M; CAPNETZ Study Group. Sphingosine Kinase 1 Regulates Inflammation and Contributes to Acute Lung Injury in Pneumococcal Pneumonia via the Sphingosine-1-Phosphate Receptor 2. Crit Care Med. 2018 Mar;46(3):e258-e267. doi: 10.1097/CCM.0000000000002916.
  • Wu WF, Fang Q, He GJ. Efficacy of corticosteroid treatment for severe community-acquired pneumonia: A meta-analysis. Am J Emerg Med. 2018 Feb;36(2):179-184. doi: 10.1016/j.ajem.2017.07.050. Epub 2017 Jul 15. Review.
  • Vettorazzi S, Bode C, Dejager L, Frappart L, Shelest E, Klaßen C, Tasdogan A, Reichardt HM, Libert C, Schneider M, Weih F, Henriette Uhlenhaut N, David JP, Gräler M, Kleiman A, Tuckermann JP. Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1. Nat Commun. 2015 Jul 17;6:7796. doi: 10.1038/ncomms8796.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 2, 2019) 		400
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2025
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Clinical symptoms suggestive community-acquired pneumonia and pneumonia severe index (PSI) > 90, Age 18 years or older and Written informed consent obtained

Exclusion Criteria:

  • Presence of severe immunosuppression (HIV infection, use of immunosuppressants), malignancy, pregnancy or breastfeeding, patient with uncontrol diabetes, current use of antibiotics or corticosteroids, any likely infection other than CAP, or pneumonia that developed within 3 days after hospital discharge
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Shih-Chang Hsu, MD 0982770936 1980bradhsu@gmail.com
Listed Location Countries  ICMJE Taiwan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04007328
Other Study ID Numbers  ICMJE N201812054
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Taipei Medical University WanFang Hospital
Study Sponsor  ICMJE Taipei Medical University WanFang Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ching-Wang Hsu, MD Wan Fang Hospital
PRS Account Taipei Medical University WanFang Hospital
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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