CRETE: Catheter-Related Early Thromboprophylaxis With Enoxaparin Studies

Sponsor

Yale University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04924322

Collaborator

Children's Healthcare of Atlanta (Other), Children's Hospital Colorado (Other), Children's Hospital of Philadelphia (Other), Virginia Commonwealth University (Other), BJC HealthCare (Other), Medical College of Wisconsin (Other), Children's of Alabama (Other), Children's Hospital Medical Center, Cincinnati (Other), Golisano Children's Hospital (Other), Maria Fareri Children's Hospital (Other), Nationwide Children's Hospital (Other), New York Presbyterian Hospital (Other), Penn State University (Other), University of Iowa (Other)

258

Enrollment

Locations

Arms

50.7

Anticipated Duration (Months)

17.2

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Deep Venous Thrombosis	Drug: Enoxaparin	Phase 2/Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

258 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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.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 (Outcomes Assessor)

Masking Description:

The CRETE Studies are open-label with blinded endpoint. Systematic ultrasonographic assessment will be performed with the images blindly and centrally adjudicated.

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

May 11, 2022

Anticipated Primary Completion Date :

Apr 30, 2026

Anticipated Study Completion Date :

Jul 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Enoxaparin (Older Children Prophylactic) Prophylactic dose of enoxaparin for older children 1-17 years old.	Drug: Enoxaparin 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. Other Names: Lovenox Clexane
No Intervention: Control (Older Children) Usual care without placebo for older children 1-17 years old.
Experimental: Enoxaparin (Infants Therapeutic High Anti-Xa Target) Therapeutic dose of enoxaparin for infants <1 year old with anti-Xa target of >0.5-1 IU/mL.	Drug: Enoxaparin 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. Other Names: Lovenox Clexane
Experimental: Enoxaparin (Infants Therapeutic Low Anti-Xa Target) Therapeutic dose of enoxaparin for infants <1 year old with anti-Xa target of 0.2-0.5 IU/mL.	Drug: Enoxaparin 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. Other Names: Lovenox Clexane
No Intervention: Control (Infants) Usual care without placebo for infants <1 year old.

Outcome Measures

Primary Outcome Measures

Number of children with CADVT [Up to removal of CVC (maximum of 28 days)]
Thrombus in the central vein where the CVC was inserted that is diagnosed with systematic ultrasonographic surveillance.

Secondary Outcome Measures

Number of children with any VTE [Up to removal of CVC (maximum of 28 days)]
Thrombus in the deep vein of any extremity or PE that is confirmed radiologically
Number of children with clinically apparent CADVT [Up to removal of CVC (maximum of 28 days)]
Any CADVT, except one that is only diagnosed with the systematic ultrasonographic surveillance.
Number of children with clinically apparent VTE [Up to removal of CVC (maximum of 28 days)]
Any VTE, except one that is only diagnosed with the systematic ultrasonographic surveillance.
Number of children with clinically relevant bleeding [Maximum of 36 hours after the last dose of enoxaparin]
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.
Number of children with any bleeding [Maximum of 36 hours after the last dose of enoxaparin]
Any overt or macroscopic evidence of bleeding.
Number of children with heparin-induced thrombocytopenia [Maximum of 36 hours after the last dose of enoxaparin]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's of Alabama	Birmingham	Alabama	United States	35233
2	Children's Hospital Colorado	Aurora	Colorado	United States	80045
3	Yale-New Haven Children's Hospital	New Haven	Connecticut	United States	06520
4	Children's Healthcare of Atlanta, Egleston	Atlanta	Georgia	United States	30322
5	Stead Family Children's Hospital	Iowa City	Iowa	United States	52242
6	Children's Hospital St. Louis	Saint Louis	Missouri	United States	63110
7	New York Presbyterian Hospital	New York	New York	United States	10065
8	Golisano Children's Hospital	Rochester	New York	United States	14642
9	Maria Fareri Children's Hospital	Valhalla	New York	United States	10595
10	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
11	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
12	Penn State Hershey Children's Hospital	Hershey	Pennsylvania	United States	17033
13	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
14	Children's Hospital of Richmond	Richmond	Virginia	United States	23219
15	Children's Hospital Wisconsin	Milwaukee	Wisconsin	United States	53226