Catheter-Related Early Thromboprophylaxis With Enoxaparin Studies

Study Overview
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Brief Summary
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The goal of the CRETE Studies is to investigate the newly identified age-dependent heterogeneity in the efficacy of enoxaparin in reducing the risk of central venous catheter-associated deep venous thrombosis in critically ill children.

Detailed Description
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Pediatric venous thromboembolism (VTE), which is predominantly deep venous thrombosis (DVT), is a top contributor to harm in hospitalized children. Its incidence increased by >300% in the past 2 decades. Critical illness and central venous catheter (CVC) are the most important risk factors for VTE in children. Among critically ill children, the risk of CVC-associated DVT (CADVT) is as high as 54% with 72% of cases in infants <1-year old. Pharmacologic prophylaxis is the most effective strategy against VTE in adults. However, due to paucity of age-appropriate evidence on its efficacy against CADVT, pharmacologic prophylaxis is uncommon in children. Extrapolation of evidence from adults is not appropriate because the hemostatic system changes significantly with age. The investigators recently completed a Bayesian phase 2b randomized clinical trial. In this trial, the investigators randomized critically ill children to early administration of prophylactic dose of enoxaparin, the most commonly used anticoagulant for prophylaxis, or usual care. Prophylaxis with enoxaparin appeared to reduce the risk of CADVT by half. In post hoc analyses, reduction was limited to older children 1-17 years old. The goal of the CRETE Studies is to investigate this newly identified age-dependent heterogeneity in the efficacy of enoxaparin in reducing the risk of CADVT in critically ill children. To achieve this goal, the investigators aim (1) to confirm the efficacy and safety of early administration of prophylactic dose of enoxaparin in reducing the risk of CADVT in critically ill older children; (2) to determine the efficacy and safety of early administration of therapeutic dose of enoxaparin in reducing the risk of CADVT in critically ill infants; and, (3) to probe the mechanisms that underly the age-dependent heterogeneity in the efficacy of enoxaparin in reducing the risk of CADVT in critically ill children. The investigators will conduct 2 multicenter Bayesian explanatory randomized clinical trials in parallel to address Specific Aims 1 and 2. Depending on age, subjects will be randomized to different doses of enoxaparin vs usual care. Subjects will be systematically assessed for the development of CADVT using ultrasonography and clinically for bleeding. Using plasma obtained from subjects in the 2 trials, the investigators will conduct an exploratory mechanistic nested case-control study to address Specific Aim 3. Biomarkers of selected mechanisms underlying CVC-associated thrombus formation, particularly thrombin generation, will be compared between subjects with and without CADVT. The investigators will use Bayesian methods to improve the efficiency in the conduct and analyses of these studies. The CRETE Studies will provide high-quality age-appropriate evidence that will inform preventive strategies against CADVT and decrease harm in hospitalized children.

Official Title
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Age-dependent Heterogeneity in the Efficacy of Prophylaxis With Enoxaparin Against Catheter-associated Thrombosis in Critically Ill Children

Conditions
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Deep Venous Thrombosis

Intervention / Treatment
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* Drug: Enoxaparin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria >36 weeks corrected gestational to <17 years old <24 hours after insertion of an untunneled CVC CVC inserted in the internal jugular or femoral vein Exclusion criteria Radiologic diagnosis of CADVT in the site of insertion in prior 6 weeks Currently receiving an antithrombotic agent, e.g., LMWH, UFH, warfarin and aspirin, but not UFH at dose to maintain patency of a vascular catheter Presence of clinically relevant bleeding, i.e., hemoglobin decreased ≥2 g/dl in 24 hours, required medical or surgical intervention to restore hemostasis, or in the retroperitoneum, pulmonary, intracranial or central nervous system, in the prior 60 days Surgery in the prior 7 days Major trauma in the prior 7 days Presence of coagulopathy, i.e., INR >2.0, aPTT >50 seconds or platelet count <50 x 10^3/mcL Presence of renal failure, i.e., creatinine clearance <30 mL/min/1.73 m2 Known hypersensitivity to heparin or pork products Laboratory confirmed HIT Current pregnancy or lactation Presence of an epidural catheter Limitation of care Previous enrollment in the CRETE Studies

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Older children 1-17 years old and infants <1 year old will be randomized separately. Older children will be randomized 2:1 to prophylactic dose of enoxaparin or control stratified by age. Infants will be randomized 1:1:1 to therapeutic dose of enoxaparin with high or low anti-Xa target or control stratified by age.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enoxaparin (Older Children Prophylactic)<br>Prophylactic dose of enoxaparin for older children 1-17 years old. | Drug: Enoxaparin<br>* Enoxaparin is a LMWH produced from UFH that exerts its anticoagulant effects by binding to and inducing a conformational change in antithrombin to accelerate the inactivation of factor Xa and thrombin. Age-specified dose of enoxaparin will be administered within 24 hours after insertion of the CVC with the dose subsequently adjusted to pre-specified anti-Xa target.<br>* Other names: Clexane;|
| No Intervention: Control (Older Children)<br>Usual care without placebo for older children 1-17 years old. | |
| Experimental: Enoxaparin (Infants Therapeutic High Anti-Xa Target)<br>Therapeutic dose of enoxaparin for infants <1 year old with anti-Xa target of >0.5-1 IU/mL. | Drug: Enoxaparin<br>* Enoxaparin is a LMWH produced from UFH that exerts its anticoagulant effects by binding to and inducing a conformational change in antithrombin to accelerate the inactivation of factor Xa and thrombin. Age-specified dose of enoxaparin will be administered within 24 hours after insertion of the CVC with the dose subsequently adjusted to pre-specified anti-Xa target.<br>* Other names: Clexane;|
| Experimental: Enoxaparin (Infants Therapeutic Low Anti-Xa Target)<br>Therapeutic dose of enoxaparin for infants <1 year old with anti-Xa target of 0.2-0.5 IU/mL. | Drug: Enoxaparin<br>* Enoxaparin is a LMWH produced from UFH that exerts its anticoagulant effects by binding to and inducing a conformational change in antithrombin to accelerate the inactivation of factor Xa and thrombin. Age-specified dose of enoxaparin will be administered within 24 hours after insertion of the CVC with the dose subsequently adjusted to pre-specified anti-Xa target.<br>* Other names: Clexane;|
| No Intervention: Control (Infants)<br>Usual care without placebo for infants <1 year old. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of children with CADVT | Thrombus in the central vein where the CVC was inserted that is diagnosed with systematic ultrasonographic surveillance. | Up to removal of CVC (maximum of 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of children with any VTE | Thrombus in the deep vein of any extremity or PE that is confirmed radiologically | Up to removal of CVC (maximum of 28 days) | 
| Number of children with clinically apparent CADVT | Any CADVT, except one that is only diagnosed with the systematic ultrasonographic surveillance. | Up to removal of CVC (maximum of 28 days) | 
| Number of children with clinically apparent VTE | Any VTE, except one that is only diagnosed with the systematic ultrasonographic surveillance. | Up to removal of CVC (maximum of 28 days) | 
| Number of children with clinically relevant bleeding | Bleeding that is fatal, with drop in hemoglobin by ≥2 g/dl in 24 hours, requires medical or surgical intervention to restore hemostasis, or in the retroperitoneum, pulmonary or central nervous system. | Maximum of 36 hours after the last dose of enoxaparin | 
| Number of children with any bleeding | Any overt or macroscopic evidence of bleeding. | Maximum of 36 hours after the last dose of enoxaparin | 
| Number of children with heparin-induced thrombocytopenia | Unexplained drop in platelet count to <50 x 10^3/mcL or by 50 percent of baseline platelet count in the ICU within 21 days following exposure to heparin, and with a positive anti-platelet factor 4 antibody. | Maximum of 36 hours after the last dose of enoxaparin | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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child, critical illness, venous thromboembolism, enoxaparin, thrombin generation, bleed