Weight-Adjusted vs Fixed Low Doses of Low Molecular Weight Heparin For Venous Thromboembolism Prevention in COVID-19 (COVI-DOSE)

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

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.

Study Overview

• Status: Completed
• Conditions: Thrombosis; Deep Vein Thrombosis; COVID; Pulmonary Embolism
• Intervention / Treatment: Drug: Enoxaparin; Drug: Enoxaparin

• Study Type: Interventional
• Enrollment (Actual): 1000
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • Amiens Academic Hospital
  • Besançon, France
    • Besançon Academic Hospital
  • Brest, France
    • Brest Academic Hospital
  • Colmar, France
    • Civil Hospital
  • Dijon, France
    • Dijon Academic Hospital
  • Le Kremlin-Bicêtre, France
    • Kremlin Bicêtre Academic Hospital
  • Lille, France
    • Lille Academic Hospital
  • Metz, France
    • Groupe Hospitalier Unéos
  • Metz, France
    • Metz-Thionville Regional Hospital
  • Montpellier, France
    • Montpellier Academic Hospital
  • Mulhouse, France
    • Emile Muller Hospital
  • Nancy, France
    • Nancy Academic Hospital
  • Paris, France
    • George Pompidou European Hospital
  • Paris, France
    • Lariboisière Academic Hospital
  • Saint-Étienne, France
    • St Etienne Academic Hospital
  • Strasbourg, France
    • Strasbourg Academic Hospital
  • Toulouse, France
    • Toulouse Academic Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low Prophylactic Dose of Low Molecular Weight Heparin; Enoxaparin, Tinzaparin, Nadroparin, Dalteparin	Drug: Enoxaparin; For example (Enoxaparin): 4000IU twice a day in patients <50kg; 5000IU twice a day in patients 50-70kg; 6000IU twice a day in patients 70-100kg; 7000IU twice a day in patients above 100kg; Other Names: Dalteparin; Tinzaparin; Nadroparin; Drug: Enoxaparin; For example (Enoxaparin): From 4000IU once a day in patients admitted in medical ward to 4000IU twice a day in patients admitted in the ICU. In patients with severe renal insufficiency (GFR=15-30 mL/min/1.73m²), LMWH doses will be reduced by 50%.; Other Names: Dalteparin; Tinzaparin; Nadroparin
Experimental: Weight-Adjusted Prophylactic Dose Low Molecular Weight Heparin; Enoxaparin, Tinzaparin, Nadroparin, Dalteparin	Drug: Enoxaparin; For example (Enoxaparin): 4000IU twice a day in patients <50kg; 5000IU twice a day in patients 50-70kg; 6000IU twice a day in patients 70-100kg; 7000IU twice a day in patients above 100kg; Other Names: Dalteparin; Tinzaparin; Nadroparin; Drug: Enoxaparin; For example (Enoxaparin): From 4000IU once a day in patients admitted in medical ward to 4000IU twice a day in patients admitted in the ICU. In patients with severe renal insufficiency (GFR=15-30 mL/min/1.73m²), LMWH doses will be reduced by 50%.; Other Names: Dalteparin; Tinzaparin; Nadroparin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Venous thromboembolism	Risk of deep vein thrombosis or pulmonary embolism or venous thromboembolism-related death	hospitalization stay (up to 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major bleeding	Risk of major bleeding defined by the ISTH	hospitalization stay (up to 28 days)
Major Bleeding and Clinically Relevant Non-Major Bleeding	Risk of Major Bleeding and Clinically Relevant Non-Major Bleeding Defined by the ISTH	hospitalization stay (up to 28 days)
Net Clinical Benefit	Risk of Venous Thromboembolism and Major Bleeding	hospitalization stay (up to 28 days) and 60 days
Venous Thromboembolism at other sites	Risk of venous thrombosis at other sites: e.g. superficial vein, catheters, hemodialysis access, ECMO, splanchnic, encephalic, upper limb	hospitalization stay (up to 28 days)
Arterial Thrombosis	Risk of arterial thrombosis at any sites	hospitalization stay (up to 28 days)
All-Cause Mortality	Risk of all-cause mortality	hospitalization stay (up to 28 days) and 60 days
Factors associated with the risk of venous thromboembolism	Identification of associations between the risk of venous thromboembolism and clinical (eg. past medical history of thrombosis, cardiovascular risk factors, treatments, severity of COVID-19) and laboratory variables (e.g. D-dimers, fibrinogen, CRP) collected in the eCRF	hospitalization stay (up to 28 days)

Collaborators and Investigators

• Sponsor: Central Hospital, Nancy, France
• Collaborators: Ministry of Health, France; University Hospital of Saint-Etienne; Grand Est Region
• Investigators: Study Director: El Mehdi Siaghy, Research and Innovation Department, Nancy University Hospital; Principal Investigator: Stéphane Zuily, MD, PhD, Nancy Academic Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2020
• Primary Completion (Actual): April 29, 2021
• Study Completion (Actual): September 14, 2021

Study Registration Dates

• First Submitted: May 1, 2020
• First Submitted That Met QC Criteria: May 1, 2020
• First Posted (Actual): May 4, 2020

Study Record Updates

• Last Update Posted (Actual): August 7, 2023
• Last Update Submitted That Met QC Criteria: August 4, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Deep Vein Thrombosis; COVID; Thrombosis; Venous Thromboembolism; Pulmonary Embolism; Low Molecular Weight Heparin
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Thrombosis; Venous Thrombosis; Thromboembolism; Venous Thromboembolism; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin; Enoxaparin sodium; Nadroparin
• Other Study ID Numbers: 2020-001709-21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No