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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
First received
Last updated
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
Health authority
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

Study Design


Related Conditions & MeSH terms


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
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