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| Name | Class |
|---|---|
| Massimo Arquati | UNKNOWN |
| Riccardo Colombo | UNKNOWN |
| Umberto Russo | UNKNOWN |
| Manuela Nebuloni |
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SINGLE CENTER PHASE III INTERVENTIONAL RANDOMIZED CONTROLLED TRIAL comparing efficacy and safety of enoxaparin at prophylactic dose (standard treatment) and enoxaparin at therapeutic dose (OFF-LABEL treatment) in 300 COVID-19 infected patients with moderate-severe respiratory failure (PaO2/FiO2<250) and/or increased D-dimer levels enrolled in different Units (Infectious disease, Internal Medicine, Emergency Medicine, Pneumology) of Azienda Socio Sanitaria Territoriale Fatebenefratelli Sacco (ASST-FBF-SACCO).
Patients with COVID-19 are at high risk of developing a venous thromboembolism (VTE) and it is essential that effective thromboprophylaxis with parenteral drugs (LMWH, UFH) is considered for all patients admitted to hospital especially in case of severe pneumonia.
The aim of the study is the evaluation of efficacy and safety of enoxaparin at prophylactic dose (standard treatment) as compared to enoxaparin at therapeutic dose (OFF-LABEL treatment) in 300 COVID-19 infected patients with moderate-severe respiratory failure (PaO2/FiO2<250) and/or increased D-dimer levels.
After the admission to different Units (Infectious disease, Internal Medicine, Emergency Medicine, Pneumology), enoxaparin at prophylactic dose (standard of care) will be prescribed to all patients.
The randomization of the single patient will be made when the the inclusion criteria (PaO2/FiO2 <250 and/or D-dimer >2000 ng/) will be satisfied. Patients with increased bleeding risk will be excluded (exclusion criteria).
Patients will be divided into two arms:
In both arms, enoxaparin treatment will be monitored clinically and with first and second line laboratory tests Venous compression ultrasound (CUS) will be performed at admission and after 7 days in case of a first negative exam and elevated D-Dimer levels, to rule out deep vein thrombosis.
Enoxaparin at prophylactic dose (4000 IU) will be maintained in all patients for 4 weeks after discharge.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Enoxaparin at prophylactic dose | Active Comparator | Enoxaparin at prophylactic dose: standard 4.000 IU QD via subcutaneous injection (6000 IU if body weight>100 kg) |
|
| Enoxaparin at therapeutic dose | Experimental | Enoxaparin at therapeutic dose : 70 U/Kg b.i.d. (every 12 h) In order to easily calculate the correct therapeutic dose of enoxaparin for each patient, a simplified categorization will be applied, as follows:
|
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Enoxaparin | Drug | subcutaneous injections |
|
| Measure | Description | Time Frame |
|---|---|---|
| Mortality rate | Mortality registered during the time frame | 30 days from enrollment |
| Progression of respiratory failure | Progression of respiratory failure defined as duration of continuous positive pressure ventilation (CPAP) | 30 days from enrollment |
| Progression of respiratory failure | Progression of respiratory failure defined as percentage of patients admitted to ICU | 30 days from enrollment |
| Progression of respiratory failure | Progression of respiratory failure defined as percentage of patients undergoing oro-tracheal intubation | 30 days from enrollment |
| Number of major bleeding episodes | Major bleeding (ISTH criteria) and/or clinically relevant non-major bleeding | up to 6 months from randomization |
| Measure | Description | Time Frame |
|---|---|---|
| Respiratory function improvement | Amelioration of the respiratory function defined as a PaO2/FiO2 increase > 300 and / or respiratory rate (RR) < 20 breaths per min | at 72 hours |
| Respiratory function improvement |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Maddalena A Wu, M.D. | ASST Fatebenefratelli Sacco | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| ASST Fatebenefratelli Sacco | Milan | 20157 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32172226 | Background | 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 Jun 25;58(7):1116-1120. doi: 10.1515/cclm-2020-0188. | |
| 32073213 | Background | 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 Apr;18(4):844-847. doi: 10.1111/jth.14768. Epub 2020 Mar 13. |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| D013927 | Thrombosis |
| D012131 | Respiratory Insufficiency |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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Not provided
| ID | Term |
|---|---|
| D017984 | Enoxaparin |
| ID | Term |
|---|---|
| D006495 | Heparin, Low-Molecular-Weight |
| D006493 | Heparin |
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |
Not provided
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| Spinello Antinori | UNKNOWN |
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Amelioration of the respiratory function defined as a PaO2/FiO2 increase > 300 and / or respiratory rate (RR) < 20 breaths per min
| 1 week from randomization |
| Number of major cardiovascular events | numbers of myocardial infarction and stroke within the time frame | 6 months from randomization |
| Deep Vein Thrombosis | Numbers of Deep Vein Thrombosis at CUS examination within the time frame | 6 months from randomization |
| 32171076 | Background | 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 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11. |
| 32167524 | Background | 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 Jul 1;180(7):934-943. doi: 10.1001/jamainternmed.2020.0994. |
| 32007143 | Background | Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30. |
| 32251717 | Background | McGonagle D, Sharif K, O'Regan A, Bridgewood C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun Rev. 2020 Jun;19(6):102537. doi: 10.1016/j.autrev.2020.102537. Epub 2020 Apr 3. |
| 32220112 | Background | Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 May;18(5):1094-1099. doi: 10.1111/jth.14817. Epub 2020 Apr 27. |
| 28963294 | Background | Iba T, Nisio MD, Levy JH, Kitamura N, Thachil J. New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey. BMJ Open. 2017 Sep 27;7(9):e017046. doi: 10.1136/bmjopen-2017-017046. |
| 17727922 | Background | Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res. 2008;122(6):743-52. doi: 10.1016/j.thromres.2006.10.026. Epub 2007 Aug 28. |
| 27975101 | Background | Poterucha TJ, Libby P, Goldhaber SZ. More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Thromb Haemost. 2017 Feb 28;117(3):437-444. doi: 10.1160/TH16-08-0620. Epub 2016 Dec 15. |
| 26064103 | Background | Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. Anti-Inflammatory Effects of Heparin and Its Derivatives: A Systematic Review. Adv Pharmacol Sci. 2015;2015:507151. doi: 10.1155/2015/507151. Epub 2015 May 12. |
| 32239799 | Background | Thachil J. The versatile heparin in COVID-19. J Thromb Haemost. 2020 May;18(5):1020-1022. doi: 10.1111/jth.14821. Epub 2020 Apr 27. No abstract available. |
| 25187545 | Background | Milewska A, Zarebski M, Nowak P, Stozek K, Potempa J, Pyrc K. Human coronavirus NL63 utilizes heparan sulfate proteoglycans for attachment to target cells. J Virol. 2014 Nov;88(22):13221-30. doi: 10.1128/JVI.02078-14. Epub 2014 Sep 3. |
| 32302462 | Background | Barrett CD, Moore HB, Yaffe MB, Moore EE. ISTH interim guidance on recognition and management of coagulopathy in COVID-19: A comment. J Thromb Haemost. 2020 Aug;18(8):2060-2063. doi: 10.1111/jth.14860. Epub 2020 Jun 14. No abstract available. |
| 23379279 | Background | Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, Kim HK, Nielsen JD, Dempfle CE, Levi M, Toh CH; The Scientific Standardization Committee on DIC of the International Society on Thrombosis Haemostasis. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost. 2013 Feb 4. doi: 10.1111/jth.12155. Online ahead of print. |
| 15842354 | Background | Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x. |
| 32437596 | Background | Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, Li WW, Li VW, Mentzer SJ, Jonigk D. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020 Jul 9;383(2):120-128. doi: 10.1056/NEJMoa2015432. Epub 2020 May 21. |
| 32367170 | Background | Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, Merdji H, Clere-Jehl R, Schenck M, Fagot Gandet F, Fafi-Kremer S, Castelain V, Schneider F, Grunebaum L, Angles-Cano E, Sattler L, Mertes PM, Meziani F; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020 Jun;46(6):1089-1098. doi: 10.1007/s00134-020-06062-x. Epub 2020 May 4. |
| 37794281 | Derived | Wu MA, Del GIovane C, Colombo R, Dolci G, Arquati M, Vicini R, Russo U, Ruggiero D, Coluccio V, Taino A, Franceschini E, Facchinetti P, Mighali P, Trombetta L, Tonelli F, Gabiati C, Cogliati C, D'Amico R, Marietta M; ETHYCO Study Group. Low-molecular-weight heparin for the prevention of clinical worsening in severe non-critically ill COVID-19 patients: a joint analysis of two randomized controlled trials. Intern Emerg Med. 2024 Jan;19(1):71-79. doi: 10.1007/s11739-023-03439-w. Epub 2023 Oct 4. |
| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D012120 | Respiration Disorders |
| D002241 |
| Carbohydrates |