Catheter-Related Early Thromboprophylaxis With Enoxaparin Studies (CRETE)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Deep Venous Thrombosis
• Intervention / Treatment: Drug: Enoxaparin

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 Type: Interventional
• Enrollment (Estimated): 258
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: E. Vincent Faustino, MD, MHS; Phone Number: 203-785-4651; Email: vince.faustino@yale.edu
• Study Contact Backup: Name: Tara McPartland, MSW, MPH; Phone Number: 203-737-7173; Email: tara.mcpartland@yale.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Recruiting
      • Children's of Alabama
      • Principal Investigator: Michele Kong, MD
      • Contact: Meghan Murdock, RN; Email: Mmdmurdock@uabmc.edu
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • Children's Hospital Colorado
      • Principal Investigator: Matt Leroue, MD
      • Contact: Yamila Sierra; Email: Yamila.Sierra@childrenscolorado.org
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • Yale-New Haven Children's Hospital
      • Contact: E. Vincent Faustino, MD, MHS
      • Contact: Matt Kluko, MD; Email: matthew.kluko@yale.edu
      • Principal Investigator: Vincent Faustino, MD, MHS
  • Florida
    • Saint Petersburg, Florida, United States, 33701
      • Recruiting
      • Johns Hopkins All Children's
      • Principal Investigator: Anthony Sochet, MD
      • Contact: Lexi Dallas; Email: adallas2@jhmi.edu
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • Stead Family Children's Hospital
      • Contact: Maureen Austin, RN, MPH, BSN; Email: Maureen-Austin@uiowa.edu
      • Principal Investigator: Madhuradhar Chegondi, MBBS, MD
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Children's Hospital St. Louis
      • Contact: Pamela Stone, RN; Email: stone.p@wustl.edu
      • Principal Investigator: Amanda Kolmar, MD
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • New York Presbyterian Hospital
      • Contact: Marianne Nellis, MD; Email: man9026@med.cornell.edu
      • Contact: Liliko Chung; Email: lhc4027@med.cornell.edu
      • Principal Investigator: Marianne Nellis, MD
    • New York, New York, United States, 10016
      • Recruiting
      • Hassenfeld Children's Hospital
      • Contact: Sandra Deygoo; Email: nagamah.deygoo@nyulangone.org
      • Principal Investigator: Michelle Ramirez, MD
    • Rochester, New York, United States, 14642
      • Recruiting
      • Golisano Children's Hospital
      • Contact: Eileen Taillie; Email: Eileen_Taillie@URMC.Rochester.edu
      • Principal Investigator: Jill Cholette, MD
    • Valhalla, New York, United States, 10595
      • Recruiting
      • Maria Fareri Children's Hospital
      • Contact: William Cuddy; Email: William.Cuddy@wmchealth.org
      • Principal Investigator: Matthew Pinto, MD
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Recruiting
      • Nationwide Children's Hospital
      • Contact: Lisa Steele Steele, RN; Email: Lisa.Steele@NationwideChildrens.org
      • Principal Investigator: Jennifer Muszynski, MD
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • University of Oklahoma
      • Contact: Tracy Jones; Email: Tracy-Jones@ouhsc.edu
      • Principal Investigator: Christine Allen, MD
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Recruiting
      • Penn State Hershey Children's Hospital
      • Contact: Debbie Spear, RN; Email: dspear@pennstatehealth.psu.edu
      • Principal Investigator: Elizabeth Kerris, MD
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
      • Principal Investigator: Christine Glau, MD
      • Contact: Alanah McKelvey; Email: mckelveya@chop.edu
  • Virginia
    • Richmond, Virginia, United States, 23219
      • Withdrawn
      • Children's Hospital of Richmond
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Children's Hospital Wisconsin
      • Contact: Sadaf Shad, MD; Email: sshad@mcw.edu
      • Principal Investigator: Hilary Schreiber, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

5

Arms and Interventions

Participant Group / 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: Clexane; Lovenox
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: Clexane; Lovenox
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: Clexane; Lovenox
No Intervention: Control (Infants); Usual care without placebo for infants <1 year old.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Children's Hospital of Philadelphia; University of Iowa; Children's Hospital Colorado; University of Oklahoma; Medical College of Wisconsin; Nationwide Children's Hospital; Penn State University; New York Presbyterian Hospital; Virginia Commonwealth University; Johns Hopkins All Children's Hospital; Children's of Alabama; BJC HealthCare; Golisano Children's Hospital; Maria Fareri Children's Hospital
• Investigators: Principal Investigator: E. Vincent Faustino, MD, MHS, Associate Professor of Pediatrics, Yale School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2022
• Primary Completion (Estimated): April 30, 2026
• Study Completion (Estimated): July 31, 2026

Study Registration Dates

• First Submitted: June 7, 2021
• First Submitted That Met QC Criteria: June 7, 2021
• First Posted (Actual): June 11, 2021

Study Record Updates

• Last Update Posted (Estimated): November 21, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: child; venous thromboembolism; critical illness; enoxaparin; thrombin generation; bleed
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Venous Thrombosis; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin
• Other Study ID Numbers: 2000030683; 1R01HD106326-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No