Catheter-Related Early Thromboprophylaxis With Enoxaparin Studies

Deep Venous Thrombosis Clinical Trial

— CRETE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04924322
• Other study ID #: 2000030683
• Secondary ID: 1R01HD106326-01
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: May 11, 2022
• Est. completion date: July 31, 2026

Study information

• Verified date: November 2023
• Source: Yale University
• Contact: E. Vincent Faustino, MD, MHS
• Phone: 203-785-4651
• Email: vince.faustino[@]yale.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 258
• Est. completion date: July 31, 2026
• Est. primary completion date: April 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 17 Years

Eligibility

Inclusion criteria

1. >36 weeks corrected gestational to <17 years old

2. <24 hours after insertion of an untunneled CVC

3. CVC inserted in the internal jugular or femoral vein

Exclusion criteria

1. Radiologic diagnosis of CADVT in the site of insertion in prior 6 weeks

2. Currently receiving an antithrombotic agent, e.g., LMWH, UFH, warfarin and aspirin, but not UFH at dose to maintain patency of a vascular catheter

3. 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

4. Surgery in the prior 7 days

5. Major trauma in the prior 7 days

6. Presence of coagulopathy, i.e., INR >2.0, aPTT >50 seconds or platelet count <50 x 10^3/mcL

7. Presence of renal failure, i.e., creatinine clearance <30 mL/min/1.73 m2

8. Known hypersensitivity to heparin or pork products

9. Laboratory confirmed HIT

10. Current pregnancy or lactation

11. Presence of an epidural catheter

12. Limitation of care

13. Previous enrollment in the CRETE Studies

Related Conditions & MeSH terms

• Deep Venous Thrombosis
• Thrombosis
• Venous Thrombosis

Intervention

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.

Locations

Country	Name	City	State
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Children's of Alabama	Birmingham	Alabama
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Penn State Hershey Children's Hospital	Hershey	Pennsylvania
United States	Stead Family Children's Hospital	Iowa City	Iowa
United States	Children's Hospital Wisconsin	Milwaukee	Wisconsin
United States	Yale-New Haven Children's Hospital	New Haven	Connecticut
United States	Hassenfeld Children's Hospital	New York	New York
United States	New York Presbyterian Hospital	New York	New York
United States	University of Oklahoma	Oklahoma City	Oklahoma
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Richmond	Richmond	Virginia
United States	Golisano Children's Hospital	Rochester	New York
United States	Children's Hospital St. Louis	Saint Louis	Missouri
United States	Johns Hopkins All Children's	Saint Petersburg	Florida
United States	Maria Fareri Children's Hospital	Valhalla	New York

Sponsors (16)

Lead Sponsor

Collaborator

Yale University

BJC HealthCare, Children's Hospital Colorado, Children's Hospital of Philadelphia, Children's of Alabama, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Golisano Children's Hospital, Johns Hopkins All Children's Hospital, Maria Fareri Children's Hospital, Medical College of Wisconsin, Nationwide Children's Hospital, New York Presbyterian Hospital, Penn State University, University of Iowa, University of Oklahoma, Virginia Commonwealth University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	Number of children with any bleeding	Any overt or macroscopic evidence of bleeding.	Maximum of 36 hours after the last dose of enoxaparin
Secondary	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