Trial Review

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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04492254




Registration number
NCT04492254
Ethics application status
Date submitted
22/07/2020
Date registered
30/07/2020
Date last updated
2/05/2022

Titles & IDs
Public title
Early Prophylactic Low-molecular-weight Heparin (LMWH) in Symptomatic COVID-19 Positive Patients
Scientific 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
Secondary ID [1] 0 0
2020-003125-39
Secondary ID [2] 0 0
TRI-08892
Universal Trial Number (UTN)
Trial acronym
ETHIC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 0 0
Condition category
Condition code
Infection 0 0 0 0
Other infectious diseases
Respiratory 0 0 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Enoxaparin

Experimental: Enoxaparin - (40 mg o/d if < 100 kg, 40 mg b/d if = 100 kg)

No Intervention: Current standard of care (no enoxaparin) - Standard of care


Treatment: Drugs: Enoxaparin
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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Hospital Admission
Timepoint [1] 0 0
21 days
Primary outcome [2] 0 0
Hospital Admission
Timepoint [2] 0 0
50 days
Primary outcome [3] 0 0
Hospital Admission
Timepoint [3] 0 0
90 days
Primary outcome [4] 0 0
Death
Timepoint [4] 0 0
21 days
Primary outcome [5] 0 0
Death
Timepoint [5] 0 0
50 days
Primary outcome [6] 0 0
Death
Timepoint [6] 0 0
90 days
Secondary outcome [1] 0 0
Bleeding (as defined by ISTH criteria)
Timepoint [1] 0 0
21 and 50 days
Secondary outcome [2] 0 0
Diagnosis of VTE
Timepoint [2] 0 0
21, 50 and 90 days

Eligibility
Key inclusion criteria
- 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.
Minimum age
55 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
27/10/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
29/11/2021
Sample size
Target
Accrual to date
Final
219
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Harry Gibbs, National Co-ordinating Investigator, The Alfred Hospital - Melbourne
Recruitment postcode(s) [1] 0 0
- Melbourne
Recruitment outside Australia
Country [1] 0 0
Belgium
State/province [1] 0 0
Brasschaat
Country [2] 0 0
South Africa
State/province [2] 0 0
Johannesburg

Funding & Sponsors
Primary sponsor type
Other
Name
Thrombosis Research Institute
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Sanofi
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief 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. 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.

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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04492254
Trial related presentations / 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.
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.
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.
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.
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.
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.
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. Erratum In: Lancet Infect Dis. 2020 Apr 15;: Lancet Infect Dis. 2020 May 4;:
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.
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.
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.
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.
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. Erratum In: JAMA. 2021 Mar 16;325(11):1113.
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. Erratum In: Lancet. 2020 Jan 30;:
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.
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.
Proschan MA. Two-stage sample size re-estimation based on a nuisance parameter: a review. J Biopharm Stat. 2005;15(4):559-74. doi: 10.1081/BIP-200062852.
Public notes

Contacts
Principal investigator
Name 0 0
Ajay Kakkar
Address 0 0
Thrombosis Research Institute
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04492254