NCT04646655

Brief 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).

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
142

participants targeted

Target at P25-P50 for phase_3 covid19

Timeline
Completed

Started Jul 2020

Longer than P75 for phase_3 covid19

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

July 27, 2020

Completed
4 months until next milestone

First Submitted

Initial submission to the registry

November 22, 2020

Completed
8 days until next milestone

First Posted

Study publicly available on registry

November 30, 2020

Completed
1.9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

October 16, 2022

Completed
7 months until next milestone

Study Completion

Last participant's last visit for all outcomes

April 30, 2023

Completed
Last Updated

July 25, 2023

Status Verified

July 1, 2023

Enrollment Period

2.2 years

First QC Date

November 22, 2020

Last Update Submit

July 22, 2023

Conditions

Covid19Thrombosis

Keywords

COVID.19ThrombosisEnoxaparinOutcomeRespiratory failureD-dimerVenous compression ultrasound

Outcome Measures

Primary Outcomes (5)

  • 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

Secondary Outcomes (4)

  • Respiratory function improvement

    at 72 hours

  • Respiratory function improvement

    1 week from randomization

  • Number of major cardiovascular events

    6 months from randomization

  • Deep Vein Thrombosis

    6 months from randomization

Study Arms (2)

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)

Drug: Enoxaparin

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: * weight \< 65 Kg: 4.000 IU b.i.d. (every 12 h) * weight ≥ 65 Kg: 6.000 IU b.i.d. (every 12 h) * weight ≥ 100 Kg: 8.000 IU b.i.d. (every 12 h) The most appropriate dose will be evaluated in patients with creatinine clearance between 30 and 50 ml/min

Drug: Enoxaparin

Interventions

EnoxaparinDRUG

subcutaneous injections

Also known as: Clexane
Enoxaparin at prophylactic doseEnoxaparin at therapeutic dose

Eligibility Criteria

Age18 Years - 80 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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

You may not qualify if:

  • 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)
  • +1 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

ASST Fatebenefratelli Sacco

Milan, 20157, Italy

Location

Related Publications (18)

  • 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.

    PMID: 32172226BACKGROUND

  • 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.

    PMID: 32073213BACKGROUND

  • 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.

    PMID: 32171076BACKGROUND

  • 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.

    PMID: 32167524BACKGROUND

  • 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.

    PMID: 32007143BACKGROUND

  • 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.

    PMID: 32251717BACKGROUND

  • 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.

    PMID: 32220112BACKGROUND

  • 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.

    PMID: 28963294BACKGROUND

  • 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.

    PMID: 17727922BACKGROUND

  • 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.

    PMID: 27975101BACKGROUND

  • 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.

    PMID: 26064103BACKGROUND

  • 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.

    PMID: 32239799BACKGROUND

  • 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.

    PMID: 25187545BACKGROUND

  • 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.

    PMID: 32302462BACKGROUND

  • 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.

    PMID: 23379279BACKGROUND

  • 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.

    PMID: 15842354BACKGROUND

  • 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.

    PMID: 32437596BACKGROUND

  • 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.

    PMID: 32367170BACKGROUND

MeSH Terms

Conditions

COVID-19ThrombosisRespiratory Insufficiency

Interventions

Enoxaparin

Condition Hierarchy (Ancestors)

Pneumonia, ViralPneumoniaRespiratory Tract InfectionsInfectionsVirus DiseasesCoronavirus InfectionsCoronaviridae InfectionsNidovirales InfectionsRNA Virus InfectionsLung DiseasesRespiratory Tract DiseasesEmbolism and ThrombosisVascular DiseasesCardiovascular DiseasesRespiration Disorders

Intervention Hierarchy (Ancestors)

Heparin, Low-Molecular-WeightHeparinGlycosaminoglycansPolysaccharidesCarbohydrates

Study Officials

  • Maddalena A Wu, M.D.

    ASST Fatebenefratelli Sacco

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 3
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Principal Investigator

Study Record Dates

First Submitted

November 22, 2020

First Posted

November 30, 2020

Study Start

July 27, 2020

Primary Completion

October 16, 2022

Study Completion

April 30, 2023

Last Updated

July 25, 2023

Record last verified: 2023-07

Data Sharing

IPD Sharing
Will not share

Locations

IT(1)