Clinical trial NCT04360824: Covid-19 Associated Coagulopathy
Official title: COVID-19-associated Coagulopathy: Safety and Efficacy of Prophylactic Anticoagulation Therapy in Hospitalized Adults With COVID-19
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: COVID 19 Associated Coagulopathy
Lead sponsor: University of Iowa
Sponsor class: OTHER
First posted: 2020-04-24
Enrollment: 176
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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).

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.

Eligibility 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

Primary outcomes:
measure: Mortality
timeFrame: 30 Days post intervention
Secondary outcomes:
measure: Number of Participants With Acute Kidney Injury
timeFrame: 30 days post intervention
measure: Number of Participants With Arterial Thrombosis
timeFrame: 30 Days post intervention
measure: Number of Participants With Venous Thrombosis
timeFrame: 30 Days post intervention
measure: Number of Participants With Major Bleeding
timeFrame: 30 Days post intervention
measure: Number of Participants With Minor Bleeding
timeFrame: 30 Days post intervention
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: La Crosse
country: United States
facility: Gundersen Health System
state: Wisconsin
Study officials:
References:
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citation: Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Apr;18(4):844-847. doi: 10.1111/jth.14768. Epub 2020 Mar 13.
citation: Lentz SR. Thrombosis in the setting of obesity or inflammatory bowel disease. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;2016(1):180-187. doi: 10.1182/asheducation-2016.1.180.
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.