Clinical trial NCT04373707: Weight-Adjusted vs Fixed Low Doses of Low Molecular Weight Heparin For Venous Thromboembolism Prevention in COVID-19
Official title: Effectiveness of Weight-adjusted Prophylactic Low Molecular Weight Heparin Doses Compared With Lower Fixed Prophylactic Doses to Prevent Venous Thromboembolism in COVID-2019. The Multicenter Randomized Controlled Open-label Trial COVI-DOSE
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: COVID
Thrombosis
Pulmonary Embolism
Deep Vein Thrombosis
Keywords: COVID
Thrombosis
Venous Thromboembolism
Pulmonary Embolism
Deep Vein Thrombosis
Low Molecular Weight Heparin
Lead sponsor: Central Hospital, Nancy, France
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
name: Grand Est Region
name: University Hospital of Saint-Etienne
First posted: 2020-05-04
Enrollment: 1000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter randomized (1:1) controlled open-label trial, stratified on disease severity (admission to ICU or not)
Primary purpose: PREVENTION

Brief summary: Worldwide observational studies indicate a significant prothrombogenic effect associated with SARS-CoV-2 infection with a high incidence of venous thromboembolism (VTE), notably life-threatening pulmonary embolism.

According to recommendations for acute medical illnesses, all COVID-19 hospitalized patients should be given VTE prophylaxis such as a low molecular weight heparin (LMWH). A standard prophylactic dose (eg. Enoxaparin 4000IU once daily) could be insufficient in obese patients and VTE has been reported in patients treated with a standard prophylactic dose.

In COVID-19 patients, guidelines from several international societies confirm the existence of an hypercoagulability and the importance of thromboprophylaxis but the "optimal dose is unknown" and comparative studies are needed.

In view of these elements, carrying out a trial comparing various therapeutic strategies for the prevention of VTE in hospitalized patients with COVID-19 constitutes a health emergency.

Thus, we hypothesize that an increased prophylactic dose of weight-adjusted LMWH would be greater than a lower prophylactic dose of LMWH to reduce the risk of life-threatening VTE in hospitalized patients. The benefit-risk balance of this increase dose will be carefully evaluated because of bleeding complications favored by possible renal / hepatic dysfunctions, drug interactions or invasive procedures in COVID-19 patients.

This multicenter randomized (1:1) open-label controlled trial will randomize hospitalized adults with COVID-19 infection to weight-adjusted prophylactic dose vs. lower prophylactic dose of LMWH.


Eligibility criteria: Inclusion Criteria:

* Adult patient hospitalized for a probable/confirmed COVID-19 infection (confirmed by serology/polymerase chain reaction or by radiologic signs of COVID-19 pneumonia in the setting of clinical and laboratory abnormalities suggestive of a SARS-CoV-2 infection)
* Signed informed consent
* Patient affiliated to the Social Security

Exclusion Criteria:

* Renal insufficiency with a GFR\<15 mL/min/1.73m²
* Acute kidney injury KDIGO3
* Prophylactic dose of low molecular weight heparin for more than 3 days
* Curative dose of low molecular weight heparin for more than 1 day
* Recurrent catheter/hemodialysis access thromboses
* ECMO required in the next 24h
* Contraindication to low molecular weight heparin
* High bleeding risk (e.g. uncontrolled severe systemic hypertension, recent major bleeding, disseminated intravascular coagulopathy, thrombocytopenia \< 75G/L)
* History of heparin-induced thrombocytopenia
* Contraindication to blood-derived products
* Impossibility to perform a doppler ultrasound of the lower limbs (e.g. above the knee amputation, severe burn injuries)
* Expected death in the next 48h
* Vulnerable subjects according to articles L. 1121-5, L. 1121-7 et L1121-8 of French Public Health Code

Primary outcomes:
measure: Venous thromboembolism
timeFrame: hospitalization stay (up to 28 days)
Secondary outcomes:
measure: Major bleeding
timeFrame: hospitalization stay (up to 28 days)
measure: Major Bleeding and Clinically Relevant Non-Major Bleeding
timeFrame: hospitalization stay (up to 28 days)
measure: Net Clinical Benefit
timeFrame: hospitalization stay (up to 28 days) and 60 days
measure: Venous Thromboembolism at other sites
timeFrame: hospitalization stay (up to 28 days)
measure: Arterial Thrombosis
timeFrame: hospitalization stay (up to 28 days)
measure: All-Cause Mortality
timeFrame: hospitalization stay (up to 28 days) and 60 days
measure: Factors associated with the risk of venous thromboembolism
timeFrame: hospitalization stay (up to 28 days)
Other outcomes:
Locations:
city: Amiens
country: France
facility: Amiens Academic Hospital
city: Besançon
country: France
facility: Besançon Academic Hospital
city: Brest
country: France
facility: Brest Academic Hospital
city: Colmar
country: France
facility: Civil Hospital
city: Dijon
country: France
facility: Dijon Academic Hospital
city: Le Kremlin-Bicêtre
country: France
facility: Kremlin Bicêtre Academic Hospital
city: Lille
country: France
facility: Lille Academic Hospital
city: Metz
country: France
facility: Groupe Hospitalier Unéos
city: Metz
country: France
facility: Metz-Thionville Regional Hospital
city: Montpellier
country: France
facility: Montpellier Academic Hospital
city: Mulhouse
country: France
facility: Emile Muller Hospital
city: Nancy
country: France
facility: Nancy Academic Hospital
city: Paris
country: France
facility: George Pompidou European Hospital
city: Paris
country: France
facility: Lariboisière Academic Hospital
city: Saint-Étienne
country: France
facility: St Etienne Academic Hospital
city: Strasbourg
country: France
facility: Strasbourg Academic Hospital
city: Toulouse
country: France
facility: Toulouse Academic Hospital
Study officials:
affiliation: Research and Innovation Department, Nancy University Hospital
name: El Mehdi Siaghy
role: STUDY_DIRECTOR
affiliation: Nancy Academic Hospital
name: Stéphane Zuily, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zuily S, Lefevre B, Sanchez O, Empis de Vendin O, de Ciancio G, Arlet JB, Khider L, Terriat B, Greigert H, Robert CS, Louis G, Trinh-Duc A, Rispal P, Accassat S, Thiery G, Montani D, Azarian R, Meneveau N, Soudet S, Le Mao R, Maurier F, Le Moing V, Quere I, Yelnik CM, Lefebvre N, Martinot M, Delrue M, Benhamou Y, Parent F, Roy PM, Presles E, Goehringer F, Mismetti P, Bertoletti L, Rossignol P, Couturaud F, Wahl D, Thilly N, Laporte S; COVI-DOSE investigators. Effect of weight-adjusted intermediate-dose versus fixed-dose prophylactic anticoagulation with low-molecular-weight heparin on venous thromboembolism among noncritically and critically ill patients with COVID-19: the COVI-DOSE trial, a multicenter, randomised, open-label, phase 4 trial. EClinicalMedicine. 2023 Jun;60:102031. doi: 10.1016/j.eclinm.2023.102031. Epub 2023 Jun 9.
citation: Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.
citation: Flumignan RL, Tinoco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD013739. doi: 10.1002/14651858.CD013739.