Enoxaparin at Prophylactic or Therapeutic Doses in COVID-19

Covid19 Clinical Trial

— EMOS-COVID  

Official title:

Enoxaparin at Prophylactic or Therapeutic Doses With Monitoring of Outcomes in Subjects Infected With COVID-19: a Pilot Study on 300 Cases Enrolled at ASST-FBF-Sacco

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04646655
• Other study ID #: HLS-02COVID19/2020
• Status: Completed
• Phase: Phase 3
• Start date: July 27, 2020
• Est. completion date: April 30, 2023

Study information

• Verified date: July 2023
• Source: ASST Fatebenefratelli Sacco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Description:

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:

• arm A: enoxaparin at prophylactic dose (standard 4.000 IU; 6000 UI if body weight>100 kg)

• arm B: enoxaparin at therapeutic dose (70 U/Kg b.i.d. every 12 h)

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 142
• Est. completion date: April 30, 2023
• Est. primary completion date: October 16, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• COVID-19 related pneumonia with moderate-severe respiratory failure (PaO2/FiO2<250) and/or markedly increased D-dimer level (>2000 ng/mL)

• Signed informed consent

Exclusion Criteria:

• age < 18 and > 80 yrs

• history of bleeding (peptic ulcer, esophageal varices, cerebral aneurysm, cancer at high risk of bleeding, cirrhosis, hemorrhagic stroke < 1 year)

• thrombocytopenia (<100 x109/L)

• anemia (Hb < 8 g/dl)

• coagulation abnormalities (PT e/o aPTT > 1.5; fibrinogen < 150 mg/dl)

• consumption coagulopathy (ISTH criteria) [15, 16]

• deep vein thrombosis or pulmonary embolism

• dual antiplatelet therapy

• ongoing anticoagulant therapy

• allergic reaction to LMWH

• previous heparin-induced thrombocytopenia

• major surgery < 1 month; neurosurgery <3 months; eye surgery <3 months

• pregnancy

• arterial hypertension (SBPS>160 mm Hg; DBP>100 mm Hg)

• renal failure (creatinine clearance 30 ml/min)

• ICU admission or endotracheal intubation

Related Conditions & MeSH terms

• COVID-19
• Covid19
• Thrombosis

Intervention

Drug:
• Enoxaparin
subcutaneous injections

Locations

Country	Name	City	State
Italy	ASST Fatebenefratelli Sacco	Milan

Sponsors (6)

Lead Sponsor	Collaborator
ASST Fatebenefratelli Sacco	Manuela Nebuloni, Massimo Arquati, Riccardo Colombo, Spinello Antinori, Umberto Russo

Country where clinical trial is conducted

Italy, 

References & Publications (18)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: JAMA Intern Med. 2020 Jul 1;180(7):1031. — View Citation

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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. Erratum In: Lancet. 2020 Mar 28;395(10229):1038. Lancet. 2020 Mar 28;395(10229):1038. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality rate	Mortality registered during the time frame	30 days from enrollment
Primary	Progression of respiratory failure	Progression of respiratory failure defined as duration of continuous positive pressure ventilation (CPAP)	30 days from enrollment
Primary	Progression of respiratory failure	Progression of respiratory failure defined as percentage of patients admitted to ICU	30 days from enrollment
Primary	Progression of respiratory failure	Progression of respiratory failure defined as percentage of patients undergoing oro-tracheal intubation	30 days from enrollment
Primary	Number of major bleeding episodes	Major bleeding (ISTH criteria) and/or clinically relevant non-major bleeding	up to 6 months from randomization
Secondary	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
Secondary	Respiratory function improvement	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
Secondary	Number of major cardiovascular events	numbers of myocardial infarction and stroke within the time frame	6 months from randomization
Secondary	Deep Vein Thrombosis	Numbers of Deep Vein Thrombosis at CUS examination within the time frame	6 months from randomization