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A Randomized Trial of Anticoagulation Strategies in COVID-19

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ClinicalTrials.gov Identifier: NCT04359277
Recruitment Status : Terminated (the PROTECT study is being transitioned to ACTIV4 ACUTE anticoagulation inpatient study)
First Posted : April 24, 2020
Last Update Posted : October 8, 2020
Sponsor:
Information provided by (Responsible Party):
NYU Langone Health

Study Description
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Brief Summary:
This is a randomized open label trial to compare effectiveness of two dosing regimens currently used for prevention of clotting events in COVID-19 positive inpatients. Both doses and routes of anticoagulation regimens are currently used in COVID-19 positive inpatients at NYU Langone Health.

Condition or disease Intervention/treatment Phase
COVID-19 Drug: Enoxaparin Higher Dose Drug: Lower-dose prophylactic anticoagulation Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 77 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The proposed study is designed as an open label randomized trial of patients hospitalized COVID-19 positive patients with an elevated D-dimer. Patients will be randomized to higher-dose (e.g. therapeutic) anticoagulation versus lower-dose (e.g. prophylactic) anticoagulation in 1:1 ratio.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Trial of Anticoagulation Strategies in COVID-19
Actual Study Start Date : April 21, 2020
Actual Primary Completion Date : September 20, 2020
Actual Study Completion Date : September 20, 2020

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Higher-dose anticoagulation Drug: Enoxaparin Higher Dose

Drug: Enoxaparin Higher Dose

  • Enoxaparin in patients with a Cr Clearance of > 30
  • Enoxaparin 1mg/kg q12 SQ hours for weight 50-150kg
  • Enoxaparin 0.75mg/kg q12 SQ hours for weight >150kg or BMI >40
  • Unfractionated IV heparin titrated to a goal antiXa of 0.3-0.5 unit/mL (may be used as an alternative)

For Enoxaparin, AntiXA testing will be done after fourth injection only for participants with BMI >40 or weight > 150 kg as per institutional policy.
Experimental: Lower-dose prophylactic anticoagulation Drug: Lower-dose prophylactic anticoagulation

Drug: Lower-dose prophylactic anticoagulation

  • Heparin 5000 units every 12 or every 8 hours or 7500 units every 8 hours for BMI > 40 or weight > 150 kg, or
  • Enoxaparin 40mg every 24 hours or 30mg every 12 hours or every 24 hours (with CrCl < 30mL/min) SQ or
  • Enoxaparin 40mg every 12 hours SQ for weight >150kg or BMI >40-50
  • Enoxaparin 60 mg every 12 hours SQ for BMI >50

For Enoxaparin, AntiXA testing will be done after fourth injection only for participants with BMI >40 or weight > 150kg as per institutional policy.

For patients that develop acute kidney injury, and received enoxaparin, transition to IV unfractionated heparin by checking antiXa when next dose of enoxaparin would be due and initiating IV heparin when antiXa <0.7 IU/mL


Outcome Measures
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Primary Outcome Measures :
  1. Composite incidence of: all-cause mortality, cardiac arrest, symptomatic deep venous thrombosis, pulmonary embolism, arterial thromboembolism, myocardial infarction, stroke, or shock [ Time Frame: 30 days ]

Secondary Outcome Measures :
  1. Score on WHO Ordinal Scale [ Time Frame: 30 days ]

    0 = Uninfected; no viral RNA detected Ambulatory

    1. = Asymptomatic; viral RNA detected
    2. = Symptomatic: Independent
    3. = Symptomatic: assistance needed Hospitalized: Mild disease
    4. = Hospitalized; no oxygen therapy
    5. = Hospitalized; oxygen by mask or nasal prongs
    6. = Hospitalized; oxygen by NIV or High flow
    7. = Intubation & Mechanical ventilation, pO2/FIO2 >/= 150 or SpO2/FIO2
    8. = Mechanical ventilation pO2/FIO2 <

    150 (SpO2/FIO2 <200) 9 = Mechanical ventilation pO2/FIO2 < 150 and vasopressors, dialysis 10 = Dead N (%)


  2. Incidence of acute kidney injury (KDIGO criteria for Acute Kidney Injury (AKI)) [ Time Frame: 30 days ]

    AKI is defined as any of the following (Not Graded):

    • Increase in SCr by X0.3 mg/dl (X26.5 lmol/l) within 48 hours; or
    • Increase in SCr to X1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or- Urine volume o0.5 ml/kg/h for 6 hours.

  3. Requirement of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) [ Time Frame: 30 days ]
  4. Cardiac injury [ Time Frame: 30 days ]
    Measured by troponin and NTproBNPlevels

  5. Hypercoagulability [ Time Frame: 30 days ]
    measured by D-dimer and fibrinogen levels

  6. Disseminated Intravascular Coagulation (DIC) Score [ Time Frame: 30 days ]

    Platelet Count >100 x 109/L 0 Points >50 - <100 x 109/L 1 Point <50 x 109/L 2 Points Increase in Fibrin-related Markers [D Dimers] No change 0 Points Moderate rise 2 Points Strong rise 3 Points Prothrombin Time [PT] Prolongation 3 s or less 0 Points >3 s but <6 s 1 Point >6 s 2 Points Fibrinogen [Clauss] Level >1.0 g/L 0 Points <1.0 g/L 1 Point

    Score 0-8

    Interpretation of Score < 5 Suggestive of non-overt/low grade DIC. Repeat in 1-2 days.

    ≥ 5 Laboratory evidence consistent with overt DIC.


  7. Length of Hospital Stay [ Time Frame: 30 days ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. >18 years of age
  2. Hospitalized patient with a diagnosis of COVID-19
  3. Elevated D-dimer within prior 48 hours. Definition of elevated D-dimer is site-determined

Exclusion Criteria:

  1. Meeting alternative indication for higher-dose anticoagulation

    1. Prevalent blood clot at the time of enrollment
    2. D-dimer >10,000 ng/ml
    3. Rapidly rising D-dimer (change in D-dimer >10X over the prior 48 hours)
    4. Prior VTE
    5. Atrial fibrillation (with a CHADS2 Score >1*)
  2. Renal failure (Creatinine clearance <15 and/or requirement of renal replacement therapies)
  3. Heparin induced thrombocytopenia within 100 days
  4. Stroke within 30 days
  5. Hemorrhagic stroke (ever)
  6. GI bleed within 6 months
  7. Platelet count <100,000
  8. Anemia with a hemoglobin <9mg/dl
  9. Pregnancy
  10. Signs of active bleeding (e.g. a whole blood or PRBC transfusion in the past 30 days)
  11. Other high bleeding risk (I.e. trauma, use of dual antiplatelet therapy)
  12. CHF, Hypertension, Age>75 years, Diabetes, Prior stroke or TIA symptoms
Contacts and Locations
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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): NCT04359277


Locations
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United States, New York
NYU Langone Health
New York, New York, United States, 10016
Sponsors and Collaborators
NYU Langone Health
Investigators
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Principal Investigator: Jeffrey Berger, MD NYU Langone Health
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: NYU Langone Health
ClinicalTrials.gov Identifier: NCT04359277    
Other Study ID Numbers: s20-00479
First Posted: April 24, 2020    Key Record Dates
Last Update Posted: October 8, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The de-identified participant data from the final research dataset used in the published manuscript will be shared upon reasonable request beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research provided the investigator who proposes to use the data executes a data use agreement with NYU Langone Health. Requests may be directed to: jeffrey.berger@nyumc.org. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
Access Criteria: Requests may be directed to: jeffrey.berger@nyumc.org. To gain access, data requestors will need to sign a data access agreement.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Enoxaparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action