Catheter-Related Early Thromboprophylaxis With Enoxaparin (CRETE) Trial

Study Overview
=================
Brief Summary
-----------------
The purpose of this phase 2a, multi-center, randomized controlled study, is to explore the efficacy of early prophylaxis against catheter-associated deep venous thrombosis (CADVT) in critically ill children.

Detailed Description
-----------------
Critical illness and the presence of a central venous catheter (CVC) are the most important risk factors for deep venous thrombosis (DVT) in children. Catheter-associated thrombosis (CADVT) is highly prevalent and associated with poor outcomes in critically ill children. Yet, based on underpowered pediatric trials, prophylaxis against CADVT is not recommended in children. The recommendation to provide prophylaxis against thrombosis in critically ill adults should not be applied to children because the hemostatic system and co-morbidities vastly differ between age groups. Pivotal trials are urgently needed to determine whether prophylaxis can prevent CADVT and its complications in critically ill children. However, the timing and extent of reduction in thrombin generation, the biochemical goal of prophylaxis, needed to prevent CADVT in children are unclear. The goal of this application is to explore the efficacy of early prophylaxis against CADVT in critically ill children. Aim 1 is to obtain preliminary evidence on the effect of early prophylaxis on the incidence of CADVT in critically ill children. Based on the natural history of CADVT, we hypothesize that among critically ill children, prophylaxis administered <24 hours after catheter insertion decreases the incidence of ultrasound-diagnosed CADVT compared with no prophylaxis. In this phase 2a trial, children admitted to the intensive care unit with a newly inserted central venous catheter will receive enoxaparin adjusted according to anti-Xa activity, a control group will not receive enoxaparin adjusted according to anti-Xa activity. Enoxaparin has become the standard pediatric anticoagulant for prophylaxis despite the absence of conclusive data. We will use Bayesian approach to determine whether further trials are warranted. Aim 2 is to evaluate the effect of an anti-Xa activity-directed prophylactic strategy on thrombin generation in critically ill children. We hypothesize that among critically ill children, standard prophylactic dose of enoxaparin adjusted by anti-Xa activity reduces thrombin generation to <700 nanomolar-minute (nM.min), as measured by endogenous thrombin potential (ETP). In non-critically ill adults, prophylactic dose of enoxaparin proven to prevent DVT reduces ETP to <700 nM.min. Endogenous thrombin potential is the best available measure of thrombin generation. We will measure endogenous thrombin potential and anti-Xa activity at multiple time points then examine their relationship in all children enrolled in the phase 2a trial. The proposed research challenges the current paradigm on prophylaxis against CADVT in children. High quality evidence is needed to prevent CADVT and its complications in this vulnerable population.

Official Title
-----------------
Prevention of Central Venous Catheter-associated Thrombosis in Critically Ill Children: A Multicenter Phase 2b Trial

Conditions
-----------------
Deep Venous Thrombosis

Intervention / Treatment
-----------------
* Drug: Enoxaparin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Untunneled CVC inserted in the internal jugular or femoral vein within the past 24 hours Child anticipated to stay in the pediatric intensive care unit ≥48 hours CVC anticipated to be required for ≥24 hours >36 weeks corrected gestational age to <18 years old Exclusion Criteria Coagulopathy (i.e., international normalized ratio >2.0, activated partial thromboplastin time >50 seconds or platelet count <50,000/mm3) Known bleeding disorder Clinically relevant bleeding as defined by the International Society on Thrombosis and Hemostasis (i.e., Hb decreased ≥2 g/dl in 24 hours, required medical or surgical intervention to restore hemostasis, or in a critical organ system [i.e., retroperitoneum, pulmonary, intracranial or central nervous system]) <60 days from a clinically relevant bleeding as defined above <7 days after trauma or surgery Anticipated surgery within 48 hours after insertion of the CVC Renal failure (i.e., creatinine clearance <30 mL/min) Presence of epidural catheter Currently taking an antithrombotic agent (e.g., low molecular weight heparin (LMWH), unfractionated heparin (UFH) at therapeutic doses, Coumadin or aspirin) Radiologically documented DVT at the site of insertion of the CVC in the previous 6 weeks Known hypersensitivity to heparin or its components, including pork products History of heparin-induced thrombocytopenia (HIT) (i.e., positive serotonin release assay) Currently pregnant Currently lactating Prior enrollment in the study Limitation of care

Ages Eligible for Study
-----------------
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible subjects will be randomized 1:1 to treatment or control.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prophylaxis with enoxaparin<br>A clinical nurse will administer enoxaparin subcutaneously <24 hours after insertion of the central venous catheter and then give enoxaparin subcutaneously every 12 hours until the removal of the catheter. | Drug: Enoxaparin<br>* The clinical nurse will give enoxaparin subcutaneously every 12 hours at the currently used starting dose of 0.75 mg/kg for children ≤2 months old or 0.5 mg/kg (maximum of 40 mg) for older children. The 1st dose will be given <24 hours after insertion of the catheter. Doses will be adjusted to target an anti-Xa level of 0.2-0.5 IU/mL.<br>* Other names: Lovenox;|
| No Intervention: Control arm<br>Participants randomized to the control arm will receive no 'placebo' intervention. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Central Venous Catheter (CVC)- Associated Deep Vein Thrombosis (DVT) | Thrombus in the central vein where the CVC was inserted that is clinically suspected then confirmed radiologically, an incidental radiologic finding, or diagnosed with the study-related active surveillance ultrasound | Up to removal of CVC, an average of 6 days | 
| Endogenous Thrombin Potential | An established measure of coagulation status and is the best method to measure thrombin generation. It directly measures the amount of thrombin generation over time capturing the effects of natural (i.e., subject's coagulation status) and pharmacological (e.g., enoxaparin) pro- and anticoagulants. Endogenous thrombin potential is measured using thrombin generation assay. | Day of, day after and day 4 after insertion of the CVC | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number With Other Thromboembolic Events | Thrombus in the deep vein of any extremity or PE that is clinically suspected then confirmed radiologically, an incidental radiologic finding, excluding DVT diagnosed with the study-related active surveillance ultrasound | Up to removal of CVC, an average of 6 days | 
| Length of Stay in the Pediatric Intensive Care Unit in Days | Duration of stay in the pediatric intensive care unit from the day of enrollment | Up to day of discharge from the pediatric intensive care unit, an average of 10 days | 
| Length of Stay in the Hospital | Duration of stay in the hospital from the day of enrollment | Up to day of discharge from the hospital, an average of 18 days | 
| Number With Clinically Relevant Bleeding | Bleeding that is fatal, associated with a decrease in hemoglobin by ≥2 g/dl in 24 hours, requires medical or surgical intervention to restore hemostasis, or is in the retroperitoneum, pulmonary, intracranial or central nervous system as defined by International Society of Thrombosis and Haemostasis | Up to 30 hours after the last enoxaparin dose | 
| Number With Laboratory Confirmed Heparin-induced Thrombocytopenia | Heparin-induced thrombocytopenia that is diagnosed with a positive serotonin release assay | Up to removal of CVC, an average of 6 days | 
| Number of Mortality | In-hospital mortality during the subject's admission | Up to day of discharge from the hospital, average of 18 days | 
| Number of Enrolled Eligible Children | Number of eligible children enrolled in the study. | Up to 24 hours after insertion of CVC | 
| Time to 1st Dose of Enoxaparin | Time to first dose of enoxaparin | Up to 48 hours after insertion of CVC | 
| Time to Target Anti-Xa Activity | Time from insertion of the CVC to time that anti-Xa activity was within 0.2-0.5 IU/mL. | Up to removal of CVC, an average of 6 days | 
| Number of Missed Doses of Enoxaparin | Number of doses of enoxaparin that were not administered. This outcome measure was only applicable to the enoxaparin arm. | Up to removal of CVC, an average of 6 days | 
| Number of Children With Ultrasound | Number of children in whom ultrasound was not performed. | Up to 24 hours after removal of CVC | 

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