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Covid-19 Associated Coagulopathy

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ClinicalTrials.gov Identifier: NCT04360824
Recruitment Status : Recruiting
First Posted : April 24, 2020
Last Update Posted : June 19, 2020
Sponsor:
Information provided by (Responsible Party):
Usha Perepu, University of Iowa

Brief Summary:
This prospective, randomized, open-label, multi-center interventional study is designed to compare the safety and efficacy of two LMWH dosing protocols in patients admitted to the University of Iowa Hospitals with COVID-19 who meet the modified ISTH Overt DIC criteria score ≥3. Patients will be randomized to standard prophylactic dose LMWH (standard of care arm) or intermediate-dose LMWH (intervention arm).

Condition or disease Intervention/treatment Phase
COVID 19 Associated Coagulopathy Drug: Intermediate dose thromboprophylaxis Drug: Standard of Care thromboprophylaxis Phase 4

Detailed Description:

Potentially eligible patients will be identified by a healthcare professional per institutional policy on privacy. The healthcare professional will assess the eligibility of the patient by performing a chart review which will include laboratory results and weight as measured on admission to the hospital. After obtaining verbal consent from the patient to be contacted for the study, a member of the research staff will approach the patient to be part of the study. The research staff will obtain informed consent from the patient/LAR before collecting any data and performing any procedures.

5.2 Trial interventions

As standard of care, hospitalized patients with confirmed COVID-19 will be monitored for coagulopathy. Daily blood tests for platelet count, prothrombin time, D-Dimer, and fibrinogen and weekly thromboelastography will be obtained, and a daily Modified ISTH Overt DIC score will be calculated (Exhibit 1). Only patients meeting all inclusion and exclusion criteria will be asked to participate in the trial. Patients will be randomized to one of two arms:

  1. Patients randomized to the standard of care arm will receive standard prophylactic dose enoxaparin (40 mg subcutaneously daily if BMI <30 kg/m2; 30 mg subcutaneously twice daily or 40 mg subcutaneously twice daily if BMI ≥ 30 kg/m2).
  2. Patients randomized to the intervention arm will receive intermediate-dose enoxaparin (1 mg/kg Subcutaneously daily if BMI <30 kg/m2 or 0.5 mg/kg Subcutaneously twice daily if BMI ≥ 30 kg/m2), with doses rounded up to the nearest dose syringe in hospitalized patients with laboratory confirmed SARS CoV-2 infection.

5.3 Dose Modifications

  1. Enoxaparin will be held if platelets decrease to <25,000/mm3. Enoxaparin will resume once platelets increase to ≥25,000/ mm3.
  2. Enoxaparin will be held if fibrinogen is <50 mg/dL. Enoxaparin will resume once fibrinogen increases to ≥50 mg/dL.
  3. Enoxaparin will be held if estimated Creatinine clearance < 15 ml/min calculated by the modified Cockcroft and Gault formula and resumed once the Creatinine Clearance is ≥15 ml/min.
  4. Enoxaparin will be held if there is a clinical suspicion for heparin induced thrombocytopenia.
  5. Enoxaparin dose will be reduced by 25% if Creatinine Clearance ≥15 and <30 ml/min calculated by the modified Cockcroft and Gault formula and increased once the estimated Creatinine Clearance is ≥30 ml/min in both the arms.

All participating patients will continue the assigned doses of enoxaparin until hospital discharge or until a clinical event occurs requiring either discontinuation of anticoagulation therapy or full therapeutic dose anticoagulation therapy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 170 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a multi-center, randomized, open-label study comparing standard prophylactic dose enoxaparin (40 mg SC daily or 30 or 40 mg SC twice daily if BMI ≥30kg/m2; standard of care arm) versus intermediate-dose enoxaparin (1 mg/kg SC daily or 0.5 mg/kg SC twice daily if BMI≥30kg/m2; intervention arm) in hospitalized patients with laboratory-confirmed SARS-CoV-2 infection.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: COVID-19-associated Coagulopathy: Safety and Efficacy of Prophylactic Anticoagulation Therapy in Hospitalized Adults With COVID-19
Actual Study Start Date : May 6, 2020
Estimated Primary Completion Date : April 16, 2021
Estimated Study Completion Date : April 16, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Standard of Care
1) Patients randomized to the standard of care arm will receive standard prophylactic dose enoxaparin (40 mg subcutaneously daily if BMI <30kg/m2 and 30 mg subcutaneously twice daily or 40 mg subcutaneously twice daily if BMI ≥ 30kg/m2).
Drug: Standard of Care thromboprophylaxis
Patients randomized to the standard of care arm will receive standard prophylactic dose enoxaparin (40 mg subcutaneously daily if BMI <30kg/m2 and 30 mg subcutaneously twice daily or 40 mg subcutaneously twice daily if BMI ≥ 30 kg/m2).

Interventional
2) Patients randomized to the intervention arm will receive intermediate-dose enoxaparin (1 mg/kg Subcutaneously daily if BMI<30 kg/m2 or 0.5 mg/kg Subcutaneously twice daily if BMI ≥ 30kg/m2).
Drug: Intermediate dose thromboprophylaxis
2) Patients randomized to the intervention arm will receive intermediate-dose enoxaparin (1 mg/kg Subcutaneously daily if BMI<30kg/m2 or 0.5 mg/kg Subcutaneously twice daily if BMI ≥ 30kg/m2).
Other Name: intermediate dose Enoxaparin




Primary Outcome Measures :
  1. Mortality [ Time Frame: 30 Days post intervention ]
    Risk of all-cause mortality


Secondary Outcome Measures :
  1. Major Bleeding [ Time Frame: 30 Days post intervention ]
    Risk of ISTH defined major bleeding

  2. Arterial Thrombosis [ Time Frame: 30 Days post intervention ]
    Risk of ischemic stroke, myocardial infarction and/or limb ischemia

  3. Venous Thromboembolism [ Time Frame: 30 Days post intervention ]
    Risk of symptomatic venous thromboembolism

  4. ICU admission, intubation/ventilation [ Time Frame: 30 Days post intervention ]
    duration of intensive care measures

  5. Packed Red Blood Cell Transfusions [ Time Frame: 30 Days post intervention ]
    The number of units of packed red blood cells transfused

  6. Platelet Transfusions [ Time Frame: 30 Days post intervention ]
    The number of units of platelets transfused

  7. Fresh Frozen Plasma Transfusions [ Time Frame: 30 Days post intervention ]
    The number of units of Fresh Frozen Plasma Transfused

  8. Cryoprecipitate Transfusions [ Time Frame: 30 Days post intervention ]
    The number of units of Cryoprecipitate Transfused

  9. Prothrombin Complex Concentrate Transfusions [ Time Frame: 30 Days post intervention ]
    The number of units of Prothrombin Complex ConcentrateTransfused


Other Outcome Measures:
  1. The endogenous thrombin potential will be determined within 24 hours of randomization and weekly for 30 days or until hospital discharge [ Time Frame: 30 days post intervention ]
    Will be performed in stored plasma using Calibrated Automated Thrombogram. The endogenous thrombin potential will be calculated in units of nM.Min.

  2. Plasma levels of cell-free DNA will be determined within 24 hours of randomization and weekly for 30 days or until hospital discharge [ Time Frame: 30 days post intervention ]
    These assays will be performed in stored plasma. Quantification of cfDNA will be performed using Qubit dsDNA HS Assay kit. Histones H4, citrullinated-histone and DNA-myeloperoxidase will be measured using commercially available ELISA kit.

  3. PAI-1 [ Time Frame: 30 days post intervention ]
    will be measured in stored plasma using a commercially available ELISA kit.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Laboratory confirmed SARS-CoV-2 infection
  • Age ≥18 years
  • Requires hospital admission for further clinical management
  • Modified ISTH Overt DIC score ≥ 3

Exclusion Criteria:

  • Indication for full therapeutic-dose anticoagulation
  • Acute venous thromboembolism (deep vein thrombosis or pulmonary embolism) within prior 3 months
  • Acute cardiovascular event within prior 3 months
  • Acute stroke (ischemic or hemorrhagic) within prior 3 months
  • Active major bleeding
  • Severe thrombocytopenia (<25,000/mm3)
  • Increased risk of bleeding, as assessed by the investigator
  • Acute or chronic renal insufficiency with Creatinine Clearance < 30 ml/min calculated by the modified Cockcroft and Gault formula
  • Weight < 40 kg
  • Known allergies to ingredients contained in enoxaparin, allergy to heparin products or history of heparin induced thrombocytopenia

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04360824


Contacts
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Contact: Usha Perepu, MBBS 319-356-2195 usha-perepu@uiowa.edu
Contact: Steven Lentz, MD, PhD 319-356-2148 steven-lentz@uiowa.edu

Locations
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United States, Iowa
University of Iowa Recruiting
Iowa City, Iowa, United States, 52242
Contact: Usha Perepu, MD    319-356-2195    usha-perepu@uiowa.edu   
Contact: Steven Lentz, MD, PhD    319-356-2148    steve-lentz@uiowa.edu   
United States, Wisconsin
Gundersen Health System Recruiting
La Crosse, Wisconsin, United States, 54601
Contact: Lori Rosenstein, MD         
Sponsors and Collaborators
University of Iowa
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Usha Perepu, Principal Investigator, University of Iowa
ClinicalTrials.gov Identifier: NCT04360824    
Other Study ID Numbers: 202004235
First Posted: April 24, 2020    Key Record Dates
Last Update Posted: June 19, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No individual participant data will be shared

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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
Additional relevant MeSH terms:
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Hemostatic Disorders
Blood Coagulation Disorders
Hematologic Diseases
Vascular Diseases
Cardiovascular Diseases
Hemorrhagic Disorders
Enoxaparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action