Trial document





This trial has been registered retrospectively.
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  DRKS00023934

Trial Description

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Title

Predictive Value of ROTEM Analysis and Standard Coagulation Tests in Hospitalized Patients with COVID-19

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Trial Acronym

ROHOCO

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URL of the Trial

[---]*

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Brief Summary in Lay Language

The aim of the study is to improve the prediction of the clinical course ad patient outcomes in hospitalized COVID-19 patients.

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Brief Summary in Scientific Language

BACKGROUND: Coagulation changes such as increased d-dimers have been shown to be good predictors of poor outcome in hospitalized patients with COVID-19 [1-6]. ROTEM has been shown to predict outcomes in patients with hemorrhagic fever and sepsis/DIC [7-11].
HYPOTHESIS: ROTEM results may add value to age, gender and SOFA score in predicting poor outcomes (ICU admission, intubation and mechanical ventilation, ECMO, or death) in hospitalized patients with COVID-19 [12-17].
METHODS: Study format: Prospective observational multicenter trial. Study population and inclusion criteria: 250 adult (≥ 18 years) CORVID-19 patients with the need for in-hospital treatment. In hospitalized COVID-19 patients, ICU admission and hospital fatality rate (HFR) was reported with 26-32% and 4-15%, respectively [18-19]. Accordingly, 65-80 ICU admissions and 10-38 deaths can be expected in 250 hospitalized COVID-19 patients. If ICU admission rate and/or mortality will be significantly lower than expected (<16% and/or <8%, respectively), the study population will be increased to 500 hospitalized COVID-19 patients. Exclusion criteria: Patients transferred from other hospitals, patients already intubated at hospital admission, and patients who in general decline ICU therapy verbally or in their patient’s provision; patients with no or negative COVID-19 testing. Patients which were assumed to be COVID-19-positive and first blood sample has been analyzed but COVID-19 testing showed negative results will be excluded from data analysis. Data from finally COVID-19-negative patients may be analyzed separately if the number of COVID-19-negative patients allow for a reasonable statistical analysis. Patients with no blood sample for ROTEM analysis within 24 hours after hospital admission will be excluded from data analysis since this blood sample is essential to predict course and outcome. Patients with missing mandatory data will be excluded from data analysis. Patients requiring ICU admission, intubation or ventilator therapy but this option is not available have to be exclude from patient’s outcome data analysis (hospital discharge vs death). Both, intended and performed treatment has to be documented. If a hospital doesn’t offer ECMO therapy is not an exclusion criterion for the study site but this has to be documented and mentioned in the methods section. For further details, see the attached ROHOCO recruitment flowchart. Blood sampling: Blood samples for ROTEM analysis (ROTEM sigma complete+hep cartridge), PT/INR, d-dimers, fibrinogen, differential blood count, and LDH (as well as CRP and IL-6) are taken and analyzed at the day of (1) hospital admission/COVID-19 confirmation (within 24 hours after hospital admission), (2) ICU admission (within 8 hours), (3) endotracheal intubation (within 8 hours), and (4) ECMO initiation (within 8 hours) (overall up to four times 3 mL citrated whole blood for ROTEM analysis; further 5 ml blood might be necessary for standard coagulation tests, differential blood count and other lab analysis if not already done as routine). ROTEM sigma device: ROTEM sigma is a closed, cartridge-based, fully-automated viscoelastic testing system with a very low risk of contamination [20]. The blood sampling vial is connected to the cartridge without opening the vial. ROTEM analysis run time should be 65-70 min in order to achieve LI60 results. Aim of the study and statistical analysis: The prognostic value of patient’s age, gender, single ROTEM parameters, a ROTEM score (combination of ROTEM parameters), d-dimers, PT/INR, fibrinogen, differential blood cell count, LDH (as well as CRP, IL-6, SpO2 and SOFA score if available) at different time points during hospital stay in predicting poor outcomes (ICU admission, intubation and mechanical ventilation, ECMO, or death) in hospitalized COVID-19 patients will be assessed by ROC curve analyses. ROTEM analysis (ROTEM sigma cartridge complete+hep), and standard coagulation tests (d-dimer, PT/INR and fibrinogen, and differential blood cell count) are mandatory – LDH, CRP, IL6, SpO2 and SOFA score are not mandatory but nice to have. A COVID-19 outcome prediction score will be developed for patients with the need for hospitalization.

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Do you plan to share individual participant data with other researchers?

No

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Description IPD sharing plan:

Not considered, yet.

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Organizational Data

  •   DRKS00023934
  •   2020/12/21
  •   [---]*
  •   yes
  •   Approved
  •   20-9242-BO, Ethik-Kommission der Medizinischen Fakultät der Universität Duisburg-Essen
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Secondary IDs

  • [---]*
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Health Condition or Problem studied

  •   U07.1 -  Emergency use of U07.1
  •   U07.2 -  Emergency use of U07.2
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Interventions/Observational Groups

  •   Observational Study.

    Study population and inclusion criteria: 250 adult (≥ 18 years) CORVID-19 patients with the need for in-hospital treatment. In hospitalized COVID-19 patients, ICU admission and hospital fatality rate (HFR) was reported with 26-32% and 4-15%, respectively [18-19]. Accordingly, 65-80 ICU admissions and 10-38 deaths can be expected in 250 hospitalized COVID-19 patients. If ICU admission rate and/or mortality will be significantly lower than expected (<16% and/or <8%, respectively), the study population will be increased to 500 hospitalized COVID-19 patients.

    Blood sampling: Blood samples for ROTEM analysis (ROTEM sigma complete+hep cartridge), PT/INR, d-dimers, fibrinogen, differential blood count, and LDH (as well as CRP and IL-6) are taken and analyzed at the day of (1) hospital admission/COVID-19 confirmation (within 24 hours after hospital admission), (2) ICU admission (within 8 hours), (3) endotracheal intubation (within 8 hours), and (4) ECMO initiation (within 8 hours) (overall up to four times 3 mL citrated whole blood for ROTEM analysis; further 5 ml blood might be necessary for standard coagulation tests, differential blood count and other lab analysis if not already done as routine).

    ROTEM sigma device: ROTEM sigma is a closed, cartridge-based, fully-automated viscoelastic testing system with a very low risk of contamination [20]. The blood sampling vial is connected to the cartridge without opening the vial. ROTEM analysis run time should be 65-70 min in order to achieve LI60 results.

    Aim of the study and statistical analysis: The prognostic value of patient’s age, gender, single ROTEM parameters, a ROTEM score (combination of ROTEM parameters), d-dimers, PT/INR, fibrinogen, differential blood cell count, LDH (as well as CRP, IL-6, SpO2 and SOFA score if available) at different time points during hospital stay in predicting poor outcomes (ICU admission, intubation and mechanical ventilation, ECMO, or death) in hospitalized COVID-19 patients will be assessed by ROC curve analyses. ROTEM analysis (ROTEM sigma cartridge complete+hep), and standard coagulation tests (d-dimer, PT/INR and fibrinogen, and differential blood cell count) are mandatory – LDH, CRP, IL6, SpO2 and SOFA score are not mandatory but nice to have. A COVID-19 outcome prediction score will be developed for patients with the need for hospitalization.
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Characteristics

  •   Non-interventional
  •   Observational study
  •   Single arm study
  •   Open (masking not used)
  •   [---]*
  •   Uncontrolled/Single arm
  •   Prognosis
  •   Single (group)
  •   N/A
  •   N/A
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Primary Outcome

Prediction of the need for intensive care, endotracheal intubation and mechanical ventilation, extracorporeal membran oxygenation (ECMO), hospital discharge or death

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Secondary Outcome

Development of a COVID-19 score

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Countries of Recruitment

  •   Germany
  •   Qatar
  •   Mexico
  •   Spain
  •   Portugal
  •   Brazil
  •   Italy
  •   France
  •   Colombia
  •   India
  •   Saudi Arabia
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
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Recruitment

  •   Actual
  •   2020/04/17
  •   500
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   100   Years
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Additional Inclusion Criteria

Suspected or proven COVID-19

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Exclusion Criteria

Patients transferred from other hospitals, patients already intubated at hospital admission, and patients who in general decline ICU therapy verbally or in their patient’s provision; patients with no or negative COVID-19 testing. Patients which were assumed to be COVID-19-positive and first blood sample has been analyzed but COVID-19 testing showed negative results will be excluded from data analysis. Data from finally COVID-19-negative patients may be analyzed separately if the number of COVID-19-negative patients allow for a reasonable statistical analysis. Patients with no blood sample for ROTEM analysis within 24 hours after hospital admission will be excluded from data analysis since this blood sample is essential to predict course and outcome. Patients with missing mandatory data will be excluded from data analysis. Patients requiring ICU admission, intubation or ventilator therapy but this option is not available have to be exclude from patient’s outcome data analysis (hospital discharge vs death). Both, intended and performed treatment has to be documented. If a hospital doesn’t offer ECMO therapy is not an exclusion criterion for the study site but this has to be documented and mentioned in the methods section.

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Addresses

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    • Universitätsklinikum Essen
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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    • Tem Innovations GmbH
    • Mr.  Dr. med.  Klaus  Görlinger 
    • Martin-Kollar-Strasse 15
    • 81829  München
    • Germany
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  • start of 1:1-Block address scientific-contact
    • Universitätsklinikum Essen
    • Mr.  Prof. Dr. med.  Daniel  Dirkmann 
    • Hufelandstrasse 55
    • 45147  Essen
    • Germany
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  • start of 1:1-Block address public-contact
    • Universitätsklinikum Essen
    • Mr.  Prof. Dr. med.  Daniel  Dirkmann 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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Sources of Monetary or Material Support

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    • Universitätsklinikum Essen
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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    end of 1:1-Block address contact materialSupport
  • start of 1:1-Block address otherSupport
    • Tem Innovations GmbH
    • Mr.  Dr. med.  Klaus  Görlinger 
    • Martin-Kollar-Strasse 15
    • 81829  München
    • Germany
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    start of 1:1-Block address contact otherSupport
    end of 1:1-Block address contact otherSupport
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Status

  •   Recruiting ongoing
  •   [---]*
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Trial Publications, Results and other Documents

  •   Literatur: 1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 11. Pii: S0140-6736(20)30566-3. Doi: 10.1016/S0140-6736(20)30566-3. [Epub ahead of print] https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2930566-3 2. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Zhou X, Du C, Zhang Y, Song J, Wang S, Chao Y, Yang Z, Xu J, Zhou X, Chen D, Xiong W, Xu L, Zhou F, Jiang J, Bai C, Zheng J, Song Y. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 Mar 13. Doi: 10.1001/jamainternmed.2020.0994. [Epub ahead of print] https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2763184 3. Liu M, He P, Liu HG, Wang XJ, Li FJ, Chen S, Lin J, Chen P, Liu JH, Li CH. [Clinical characteristics of 30 medical workers infected with new coronavirus pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Mar 12;43(3):209-214. Doi: 10.3760/cma.j.issn.1001-0939.2020.03.014. Chinese. https://www.ncbi.nlm.nih.gov/pubmed/32164090 4. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Feb 19. Doi: 10.1111/jth.14768. [Epub ahead of print] https://onlinelibrary.wiley.com/doi/epdf/10.1111/jth.14768 5. Gao Y, Li T, Han M, Li X, Wu D, Xu Y, Zhu Y, Liu Y, Wang X, Wang L. Diagnostic Utility of Clinical Laboratory Data Determinations for Patients with the Severe COVID-19. J Med Virol. 2020 Mar 17. Doi: 10.1002/jmv.25770. [Epub ahead of print] https://onlinelibrary.wiley.com/doi/pdf/10.1002/jmv.25770 6. Han H, Yang L, Liu R, Liu F, Wu KL, Li J, Liu XH, Zhu CL. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med. 2020 Mar 16. Pii: /j/cclm.ahead-of-print/cclm-2020-0188/cclm-2020-0188.xml. doi: 10.1515/cclm-2020-0188. [Epub ahead of print] https://www.degruyter.com/downloadpdf/j/cclm.ahead-of-print/cclm-2020-0188/cclm-2020-0188.pdf 7. Scarlatescu E, Lance MD. Crimean-Congo haemorrhagic fever: test early with ROTEM? Lancet Infect Dis. 2019 Aug;19(8):796-797. https://www.thelancet.com/action/showPdf?pii=S1473-3099%2819%2930298-1 8. Fletcher TE, Leblebicioglu H, Bozkurt I, Sunbul M, Bilek H, Asik Z, Barut S, Gunes F, Gemici U, Hewson R, Wilson D, O’Shea MK, Woolley T, Faragher B, Parmar K, Lalloo DG, Beeching NJ, Hunt BJ. Rotational thromboelastometry alongside conventional coagulation testing in patients with Crimean-Congo haemorrhagic fever: an observational cohort study. Lancet Infect Dis. 2019 Aug;19(8):862-871. https://www.thelancet.com/action/showPdf?pii=S1473-3099%2819%2930112-4 9. Piza FM, Corrêa TD, Marra AR, Guerra JC, Rodrigues RD, Villarinho AA, de Aranda VF, Shiramizo SC, de Lima MR, Kallas EG, Cavalcanti AB. Thromboelastometry analysis of thrombocytopenic dengue patients: a cross-sectional study. BMC Infect Dis. 2017 Jan 19;17(1):89. https://bmcinfectdis.biomedcentral.com/track/pdf/10.1186/s12879-017-2204-4 10. Müller MCA, Meijers JC, van Meenen DM, Thachil J, Juffermans NP. Thromboelastometry in critically ill patients with disseminated intravascular coagulation. Blood Coagul Fibrinolysis. 2019 Jul;30(5):181-187. https://www.ncbi.nlm.nih.gov/pubmed/31157682 11. Koami H, Sakamoto Y, Ohta M, Goto A, Narumi S, Imahase H, Yahata M, Miike T, Iwamura T, Yamada KC, Inoue S. Can rotational thromboelastometry predict septic disseminated intravascular coagulation? Blood Coagul Fibrinolysis. 2015 Oct;26(7):778-83. https://www.ncbi.nlm.nih.gov/pubmed/26196197 12. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Feb 28. Doi: 10.1056/NEJMoa2002032. [Epub ahead of print] https://www.nejm.org/doi/pdf/10.1056/NEJMoa2002032 13. Kluge S, Janssens U, Welte T, Weber-Carstens S, Marx G, Karagiannidis C. [Recommendations for critically ill patients with COVID-19]. [Article in German] Med Klin Intensivmed Notfmed. 2020 Apr;115(3):175-177. https://link.springer.com/article/10.1007/s00063-020-00674-3 14. MacLaren G, Fisher D, Brodie D. Preparing for the Most Critically Ill Patients With COVID-19: The Potential Role of Extracorporeal Membrane Oxygenation. JAMA. 2020 Feb 19. doi: 10.1001/jama.2020.2342. [Epub ahead of print] https://jamanetwork.com/journals/jama/fullarticle/2761778 15. Henry BM. COVID-19, ECMO, and lymphopenia: a word of caution. Lancet Respir Med. 2020 Mar 13. pii: S2213-2600(20)30119-3. doi: 10.1016/S2213-2600(20)30119-3. [Epub ahead of print] https://www.thelancet.com/action/showPdf?pii=S2213-2600%2820%2930119-3 16. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 Feb 24. pii: S2213-2600(20)30079-5. doi: 10.1016/S2213-2600(20)30079-5. [Epub ahead of print] https://www.thelancet.com/action/showPdf?pii=S2213-2600%2820%2930079-5 17. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 Mar 3. doi: 10.1007/s00134-020-05991-x. [Epub ahead of print] https://link.springer.com/content/pdf/10.1007/s00134-020-05991-x.pdf 18. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Feb 7. Doi: 10.1001/jama.2020.1585. [Epub ahead of print] https://jamanetwork.com/journals/jama/fullarticle/2761044 19. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2930183-5 20. Schenk B, Görlinger K, Treml B, Tauber H, Fries D, Niederwanger C, Oswald E, Bachler M. A comparison of the new ROTEM sigma with its predecessor, the ROTEM delta. Anaesthesia. 2019 Mar;74(3):348-356. https://onlinelibrary.wiley.com/doi/epdf/10.1111/anae.14542
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* This entry means the parameter is not applicable or has not been set.