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COVID-19Phase 3ETHICNCT04492254

Early Prophylactic Low-molecular-weight Heparin (LMWH) in Symptomatic COVID-19 Positive Patients

A Phase 3 study testing Enoxaparin in people with COVID-19, run by Thrombosis Research Institute at 3 sites in 3 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

Evidence has shown that COVID-19 infections can lead to an increased risk of blood clots. These blood clots can lead to individuals being admitted to hospital, or, unfortunately in severe cases, death. Read more about this study

Who is it for?
Ages 55 years and older
Conditions the study is for
COVID-19
What is being tested?
Enoxaparin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
219 participants
Where
3 sitesin 3 countries
Study dates
27 Oct 2020to 29 Nov 2021
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 55 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Signed Informed consent
  • Confirmed COVID-19 (i.e. symptoms + positive test for SARS-CoV-2)
  • Male or female, age ≥ 55 years
  • At least two of the following additional risk factors:
  • Age ≥ 70 years Body mass index > 25 kg/m2 Chronic obstructive pulmonary disease (COPD) Diabetes Cardiovascular disease Corticosteroid use
  • Defined as any disease requiring medical intervention or treatment.

Who cannot join

  • Contraindications to unfractionated heparin or LMWH
  • Recent (<48 hours) or planned spinal or epidural anesthesia or puncture, PCI or thrombolytic therapy within the preceding 24 hours
  • Increased risk for bleeding complications
  • Pregnant women
  • Severe renal impairment (GFR < 30 mL/min)
  • Receiving any antiplatelet therapy (with the exception of low dose (≤100mg) aspirin) or anticoagulant therapy (e.g. VKA, DOAC)
  • Patients participating in an interventional study that is outside the purview of TRI sponsored studies.

Trial locations and contacts

3 sites in 3 countries.

3 sites in 3 countries

Australia1 site
  • Harry Gibbs, National Co-ordinating Investigator, The Alfred Hospital

    Melbourne

Other trials in Australia

Belgium1 site
  • Dr Frank Cools, National Co-ordinating Investigator, AZ Klina

    Brasschaat

Other trials in Belgium

South Africa1 site
  • Prof. Barry Jacobson, National Coordinating Investigator, University of the Witwatersrand

    Johannesburg

Other trials in South Africa

About this study

Official title: Early Thromboprophylaxis in COVID-19 (ETHIC Trial): an Open Label, Randomized Phase IIIb Trial of Community-based (LMWH) Versus Standard of Care (no Enoxaparin) in COVID-19 Positive Patients

Evidence has shown that COVID-19 infections can lead to an increased risk of blood clots. These blood clots can lead to individuals being admitted to hospital, or, unfortunately in severe cases, death. Enoxaparin is a blood-thinning drug which has been used by doctors and nurses in hospitals for many years to prevent the thickening of blood which may lead to a clot. It is easier for doctors to prevent new blood clots from forming than treating existing blood clots.

Currently, there are no treatments for COVID-19. There is an urgent need to find a safe and effective treatment to prevent worsening of the disease that may lead to hospital admission and/or death. The ETHIC (Early Thromboprophylaxis in COVID-19) study aims to find out if giving enoxaparin in an early stage of the COVID-19 disease can prevent individuals being admitted to hospital and/or death. The study will take place in approximately 8 to 10 countries, in approximately 30 to 50 centres.

Read more

Patients will be allowed to take part if they have had a confirmed COVID-19 infection, are ≥ 55 years of age and have at least two of the following additional risk factors; age ≥ 70 years, body mass index > 25 kg/m2, chronic obstructive pulmonary disease, diabetes, cardiovascular disease, or corticosteroid use.

Half the patients in the study will receive the blood-thinning drug enoxaparin for three weeks, and half will receive no treatment. Individuals will be randomly allocated to one of these groups. After 21 days, the number of patients in each group who were either admitted to hospital, or died, will be compared. The number of patients in each group who developed a blood clot (venous thromboembolism) will also be compared. Further comparisons will be made at both 50 and 90 days after the beginning of the study.

Read the detailed description

This is an open label randomized controlled trial of symptomatic individuals with confirmed COVID-19 in a community setting.

Justification: There is currently no standard of care treatment for Covid-19.

Upon enrolment into the study, patients will be randomised to receive either enoxaparin (40 mg once per day if < 100 kg, 40 mg twice per day if ≥ 100 kg) or the current standard of care (no enoxaparin) for three weeks (21 days). Randomisation must occur within 5 days of the SARS-CoV-2 test. Data will be collected at baseline and 21 days, with further assessments at 50 and 90 days.

Participants randomised to enoxaparin will receive pre-loaded syringes as part of the study, and information regarding self-administration will be provided by the sponsor. Participants in the control arm of this study will receive no treatment (current standard of care).

Screening Phase:

Investigator sites will be selected to represent community care in each country (from general practice/office based care settings, testing centres and hospitals) and invited to participate. All individuals satisfying the inclusion/exclusion criteria will be considered for enrolment and their medical history checked to exclude any patients not suitable.

Participants will be provided with a patient information sheet and consent form (PISCF), either paper or an electronic version. All participants must provide informed consent by reviewing and discussing the PISCF and by completing and signing the consent form (paper version or the electronic version). Once informed consent has been obtained, data related to baseline will be collected from a review of the participants' medical records and entered into the electronic data capture system.

Treatment Phase:

Data related to clinical outcomes for both the primary outcome (composite of hospitalisation and/or death) and secondary safety outcome (major bleeding) will be measured at 21 days. This time point will be used as a marker for collection of all data from the preceding period.

Safety and Monitoring Phase:

Data related to all outcomes will be again measured at 50 days. This time point will be used as a marker for collection of all data from the preceding period to evaluate the incidence of bleeding in all participants.

End of Study and Follow-up Phase:

The outcomes of death and hospitalisation will be further recorded 90 days after randomisation. This time point will be used as a marker for collection of all information from the interim period. The end of the trial will occur immediately following the last visit/data item of the last patient undergoing the trial. The aim of data collection will be to accurately capture all planned and unplanned visits, interruptions to treatment and events.

In case no patient data have been recorded in the participant's medical records at the site during the months following the last data entry, a follow-up phone contact will be made by the site and documented to verify that all events are being captured and participants are not lost to follow up.

The schedule of assessments is as follows: Reference: Section 6.5 of the protocol. Pages 27 to 29.

Conditions
COVID-19
Being tested
Enoxaparin
Keywords
Low Molecular Weight Heparin, Enoxaparin
Medical subject headings
COVID-19

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EnoxaparinDrug

    Also called Lovenox/Clexane

    The treatment provided will be enoxaparin sodium 40mg/0.4 mL. All doses will be provided in pre-filled, single-dose syringes for subcutaneous injection.

Study groups in NCT04492254
Study groupRoleWhat they receive
EnoxaparinExperimental(40 mg o/d if < 100 kg, 40 mg b/d if ≥ 100 kg)
Receives: Drug: Enoxaparin
Current standard of care (no enoxaparin)No interventionStandard of care

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Hospital Admission

    Hospital admission including:

    Pneumonia Acute Respiratory distress syndrome Admission to intensive care unit (ICU) Mechanical ventilation (MV)/intubation requirement Continuous positive airway pressure (CPAP)/Non-invasive ventilation Extracorporeal membrane oxygenation (ECMO)

    Measured: 21 days

  2. Hospital Admission

    Hospital admission including:

    Pneumonia Acute Respiratory distress syndrome Admission to intensive care unit (ICU) Mechanical ventilation (MV)/intubation requirement Continuous positive airway pressure (CPAP)/Non-invasive ventilation Extracorporeal membrane oxygenation (ECMO)

    Measured: 50 days

  3. Hospital Admission

    Hospital admission including:

    Pneumonia Acute Respiratory distress syndrome Admission to intensive care unit (ICU) Mechanical ventilation (MV)/intubation requirement Continuous positive airway pressure (CPAP)/Non-invasive ventilation Extracorporeal membrane oxygenation (ECMO)

    Measured: 90 days

  4. Death

    All-cause Cardiovascular Non-Cardiovascular Specific causes Fatal bleed

    Measured: 21 days

  5. Death

    All-cause Cardiovascular Non-Cardiovascular Specific causes Fatal bleed

    Measured: 50 days

  6. Death

    All-cause Cardiovascular Non-Cardiovascular Specific causes Fatal bleed

    Measured: 90 days

Secondary outcomes (2)
  1. Bleeding (as defined by ISTH criteria)

    Frequency Location Treatment (transfusion and units of blood products transfused) Severity (classified as major, clinically relevant non-major and minor)

    Measured: 21 and 50 days

  2. Diagnosis of VTE

    Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE)

    Measured: 21, 50 and 90 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Jul 2020
  2. Study start27 Oct 2020
  3. Primary completion29 Nov 2021
  4. Study completion29 Nov 2021

Why it stopped: Average event rate (end point) was much lower than expected. A larger sample size would have been required to maintain same statistical power, which was not achievable in a feasible time scale. No safety concerns were identified with bleeding.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Open label, multicentre, multi-national, randomized controlled trial.
Masking
None (open label)
Enrolment
219 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04492254
Sponsor's protocol ID
TRI-08892
Other IDs
2020-003125-39
Acronym
ETHIC
Status last verified
Apr 2022
First submitted
22 Jul 2020
Last updated
2 May 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 32073213
  • Spiezia L, Boscolo A, Poletto F, Cerruti L, Tiberio I, Campello E, Navalesi P, Simioni P. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Thromb Haemost. 2020 Jun;120(6):998-1000. doi: 10.1055/s-0040-1710018. Epub 2020 Apr 21.

    PubMed 32316063
  • Escher R, Breakey N, Lammle B. Severe COVID-19 infection associated with endothelial activation. Thromb Res. 2020 Jun;190:62. doi: 10.1016/j.thromres.2020.04.014. Epub 2020 Apr 15. No abstract available.

    PubMed 32305740
  • 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.

    PubMed 32220112
  • Peng YD, Meng K, Guan HQ, Leng L, Zhu RR, Wang BY, He MA, Cheng LX, Huang K, Zeng QT. [Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV]. Zhonghua Xin Xue Guan Bing Za Zhi. 2020 Jun 24;48(6):450-455. doi: 10.3760/cma.j.cn112148-20200220-00105. Chinese.

    PubMed 32120458
  • Lighter J, Phillips M, Hochman S, Sterling S, Johnson D, Francois F, Stachel A. Obesity in Patients Younger Than 60 Years Is a Risk Factor for COVID-19 Hospital Admission. Clin Infect Dis. 2020 Jul 28;71(15):896-897. doi: 10.1093/cid/ciaa415. No abstract available.

    PubMed 32271368
  • Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, Cuomo-Dannenburg G, Thompson H, Walker PGT, Fu H, Dighe A, Griffin JT, Baguelin M, Bhatia S, Boonyasiri A, Cori A, Cucunuba Z, FitzJohn R, Gaythorpe K, Green W, Hamlet A, Hinsley W, Laydon D, Nedjati-Gilani G, Riley S, van Elsland S, Volz E, Wang H, Wang Y, Xi X, Donnelly CA, Ghani AC, Ferguson NM. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020 Jun;20(6):669-677. doi: 10.1016/S1473-3099(20)30243-7. Epub 2020 Mar 30.

    PubMed 32240634
  • Banerjee A, Pasea L, Harris S, Gonzalez-Izquierdo A, Torralbo A, Shallcross L, Noursadeghi M, Pillay D, Sebire N, Holmes C, Pagel C, Wong WK, Langenberg C, Williams B, Denaxas S, Hemingway H. Estimating excess 1-year mortality associated with the COVID-19 pandemic according to underlying conditions and age: a population-based cohort study. Lancet. 2020 May 30;395(10238):1715-1725. doi: 10.1016/S0140-6736(20)30854-0. Epub 2020 May 12.

    PubMed 32405103
  • 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.

    PubMed 15842354
  • Kaatz S, Ahmad D, Spyropoulos AC, Schulman S; Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015 Nov;13(11):2119-26. doi: 10.1111/jth.13140. No abstract available.

    PubMed 26764429
  • Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ. 2020 Apr 2;369:m1375. doi: 10.1136/bmj.m1375. No abstract available.

    PubMed 32241884
  • 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 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585.

    PubMed 32031570
  • 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. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24.

    PubMed 31986264
  • Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.

    PubMed 32192578
  • 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.

    PubMed 26064103

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Enoxaparin in people with COVID-19, run by Thrombosis Research Institute at 3 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 2 May 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Australia, Belgium, South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Average event rate (end point) was much lower than expected. A larger sample size would have been required to maintain same statistical power, which was not achievable in a feasible time scale. No safety concerns were identified with bleeding.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Hospital Admission (time frame: 21 days). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04492254, which also lists 18 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 May 2022.

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