ETHIC trial: Early LMWH in symptomatic COVID-19 positive patients [COVID-19]
Research type
Research Study
Full title
Early thromboprophylaxis in COVID-19 (ETHIC trial): an open label, randomized phase IIIb trial of community-based prophylactic low-molecular-weight heparin (LMWH) versus standard of care (no enoxaparin) in COVID-19 positive patients
IRAS ID
286441
Contact name
Ajay K. Kakkar Kakkar
Contact email
Sponsor organisation
CYTE Global
Eudract number
2020-003125-39
Clinicaltrials.gov Identifier
Duration of Study in the UK
0 years, 6 months, 15 days
Research summary
Research Summary
Evidence has shown that COVID-19 infections can lead to an increased risk of blood clots. Unfortunately, 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 a small dose of the blood-thinning drug enoxaparin for three weeks, and half will receive no enoxaparin 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.
Summary of Results
Recent evidence suggests that severe COVID-19 infections are associated with a profound prothrombotic state and large and small vessel thrombosis. The view is emerging that thrombosis in small pulmonary arteries is intrinsically involved in the acute respiratory distress syndrome (ARDS) seen in severe COVID-19.
A number of changes in coagulation tests have been reported in patients with COVID-19 including elevation of factor VIII, fibrinogen and D-dimer [1-3]. D-dimer, in particular, has been found to be extremely raised in many patients and to be a marker of poor outcomes [4]. It is thought that the elevation in D-dimer and other coagulation disturbances are linked to the inflammatory response to the viral infection in some patients as well as the significant hypoxia that is typically observed.
Prophylactic anticoagulation with low molecular weight heparin (LMWH) has recently been shown to reduce mortality in hospitalised patients with severe COVID-19 [5]. Given the recognised efficacy of LMWH in primary thromboprophylaxis in general medical and surgical patients, and the benefit of avoiding progression of COVID-19 to a severe stage requiring hospital admission, there is a clear need to evaluate the role of early administration of LMWH thromboprophylaxis in the community in patients with COVID-19 at an early stage of their illness before the pathological process has taken hold. Additionally, heparin has recently been shown to cause a conformational change to the SARS-CoV-2 surface protein S1 receptor binding domain [6].
The Early thromboprophylaxis in COVID-19 (ETHIC) trial is an open label, randomized phase IIIb trial of community-based prophylactic LMWH versus standard of care (no enoxaparin) in COVID-19 positive patients. The trial was conducted at 15 centres in six countries (Belgium, Brazil, India, South Africa, Spain, and the UK). Between Oct 27, 2020, and Nov 8, 2021 219 eligible patients were enrolled. The eligibility criteria were being at least 30 years old, having not received a COVID-19 vaccine, and having symptomatic, confirmed COVID-19 in the outpatient setting, in addition to at least one risk factor for severe disease.
Within 9 days of symptom onset, eligible participants were randomly assigned (1:1) to receive either subcutaneous enoxaparin for 21 days (40 mg once daily if they weighed <100 kg and 40 mg twice daily if they weighed ≥100 kg) or standard of care (without enoxaparin). The primary efficacy endpoint was the composite of all-cause hospitalisation and all-cause mortality at 21 days after randomisation. Safety was also analysed in the intention-to-treat population which formed part of the main analysis.
Median follow-up in both groups was 21 days (IQR 21–21) and there was no difference in the composite of all-cause mortality and hospitalisation at 21 days between the enoxaparin group (12 [11%] of 105 patients) and the standard-of-care group (12 [11%] of 114 patients; unadjusted hazard ratio 1·09 [95% CI 0·49–2·43]; log-rank p=0·83). At 21 days, two (2%) of 105 patients in the enoxaparin group (one minor bleed and one bleed of unknown severity) and one (1%) of 114 patients in the standard-of-care group (major abnormal uterine bleeding) had a bleeding event. 22 (21%) patients in the enoxaparin group and 13 (11%) patients in the standard-of-care group had adverse events. The most common adverse event in both groups was COVID-19-related pneumonia (six [6%] patients in the enoxaparin group and five [4%] patients in the standard-of-care group). One patient in the enoxaparin group died and the cause of death was unknown.
The study required a sample size of 1370 patients but following the advice of the Data and Safety Monitoring Board, it was terminated early due to slow enrolment and a lower-than-expected event rate. However, the results from the set of patients enrolled in the ETHIC trial indicated no benefit for prophylaxis with low-molecular-weight heparin in at-risk outpatients with COVID-19.REC name
North East - York Research Ethics Committee
REC reference
20/NE/0242
Date of REC Opinion
15 Oct 2020
REC opinion
Further Information Favourable Opinion