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Catheter-Related Early Thromboprophylaxis With Enoxaparin Studies (CRETE)

Primary Purpose

Deep Venous Thrombosis

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Enoxaparin
Sponsored by
Yale University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Deep Venous Thrombosis focused on measuring child, critical illness, venous thromboembolism, enoxaparin, thrombin generation, bleed

Eligibility Criteria

undefined - 17 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Children's of AlabamaRecruiting
  • Children's Hospital ColoradoRecruiting
  • Yale-New Haven Children's HospitalRecruiting
  • Johns Hopkins All Children'sRecruiting
  • Stead Family Children's HospitalRecruiting
  • Children's Hospital St. LouisRecruiting
  • Hassenfeld Children's HospitalRecruiting
  • New York Presbyterian HospitalRecruiting
  • Golisano Children's HospitalRecruiting
  • Maria Fareri Children's HospitalRecruiting
  • Nationwide Children's HospitalRecruiting
  • University of OklahomaRecruiting
  • Penn State Hershey Children's HospitalRecruiting
  • Children's Hospital of Philadelphia
  • Children's Hospital of RichmondRecruiting
  • Children's Hospital WisconsinRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

No Intervention

Experimental

Experimental

No Intervention

Arm Label

Enoxaparin (Older Children Prophylactic)

Control (Older Children)

Enoxaparin (Infants Therapeutic High Anti-Xa Target)

Enoxaparin (Infants Therapeutic Low Anti-Xa Target)

Control (Infants)

Arm Description

Prophylactic dose of enoxaparin for older children 1-17 years old.

Usual care without placebo for older children 1-17 years old.

Therapeutic dose of enoxaparin for infants <1 year old with anti-Xa target of >0.5-1 IU/mL.

Therapeutic dose of enoxaparin for infants <1 year old with anti-Xa target of 0.2-0.5 IU/mL.

Usual care without placebo for infants <1 year old.

Outcomes

Primary Outcome Measures

Number of children with CADVT
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
Thrombus in the deep vein of any extremity or PE that is confirmed radiologically
Number of children with clinically apparent CADVT
Any CADVT, except one that is only diagnosed with the systematic ultrasonographic surveillance.
Number of children with clinically apparent VTE
Any VTE, except one that is only diagnosed with the systematic ultrasonographic surveillance.
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.
Number of children with any bleeding
Any overt or macroscopic evidence of bleeding.
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.

Full Information

First Posted
June 7, 2021
Last Updated
May 31, 2023
Sponsor
Yale University
Collaborators
Children's Hospital Colorado, Children's Hospital of Philadelphia, Virginia Commonwealth University, BJC HealthCare, Medical College of Wisconsin, Children's of Alabama, Golisano Children's Hospital, Maria Fareri Children's Hospital, Nationwide Children's Hospital, New York Presbyterian Hospital, Penn State University, University of Iowa, Johns Hopkins All Children's Hospital, University of Oklahoma, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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1. Study Identification

Unique Protocol Identification Number
NCT04924322
Brief Title
Catheter-Related Early Thromboprophylaxis With Enoxaparin Studies
Acronym
CRETE
Official Title
Age-dependent Heterogeneity in the Efficacy of Prophylaxis With Enoxaparin Against Catheter-associated Thrombosis in Critically Ill Children
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 11, 2022 (Actual)
Primary Completion Date
April 30, 2026 (Anticipated)
Study Completion Date
July 31, 2026 (Anticipated)

3. Sponsor/Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Deep Venous Thrombosis
Keywords
child, critical illness, venous thromboembolism, enoxaparin, thrombin generation, bleed

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
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.
Masking
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.
Allocation
Randomized
Enrollment
258 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Enoxaparin (Older Children Prophylactic)
Arm Type
Experimental
Arm Description
Prophylactic dose of enoxaparin for older children 1-17 years old.
Arm Title
Control (Older Children)
Arm Type
No Intervention
Arm Description
Usual care without placebo for older children 1-17 years old.
Arm Title
Enoxaparin (Infants Therapeutic High Anti-Xa Target)
Arm Type
Experimental
Arm Description
Therapeutic dose of enoxaparin for infants <1 year old with anti-Xa target of >0.5-1 IU/mL.
Arm Title
Enoxaparin (Infants Therapeutic Low Anti-Xa Target)
Arm Type
Experimental
Arm Description
Therapeutic dose of enoxaparin for infants <1 year old with anti-Xa target of 0.2-0.5 IU/mL.
Arm Title
Control (Infants)
Arm Type
No Intervention
Arm Description
Usual care without placebo for infants <1 year old.
Intervention Type
Drug
Intervention Name(s)
Enoxaparin
Other Intervention Name(s)
Lovenox, Clexane
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of children with CADVT
Description
Thrombus in the central vein where the CVC was inserted that is diagnosed with systematic ultrasonographic surveillance.
Time Frame
Up to removal of CVC (maximum of 28 days)
Secondary Outcome Measure Information:
Title
Number of children with any VTE
Description
Thrombus in the deep vein of any extremity or PE that is confirmed radiologically
Time Frame
Up to removal of CVC (maximum of 28 days)
Title
Number of children with clinically apparent CADVT
Description
Any CADVT, except one that is only diagnosed with the systematic ultrasonographic surveillance.
Time Frame
Up to removal of CVC (maximum of 28 days)
Title
Number of children with clinically apparent VTE
Description
Any VTE, except one that is only diagnosed with the systematic ultrasonographic surveillance.
Time Frame
Up to removal of CVC (maximum of 28 days)
Title
Number of children with clinically relevant bleeding
Description
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.
Time Frame
Maximum of 36 hours after the last dose of enoxaparin
Title
Number of children with any bleeding
Description
Any overt or macroscopic evidence of bleeding.
Time Frame
Maximum of 36 hours after the last dose of enoxaparin
Title
Number of children with heparin-induced thrombocytopenia
Description
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.
Time Frame
Maximum of 36 hours after the last dose of enoxaparin

10. Eligibility

Sex
All
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
E. Vincent Faustino, MD, MHS
Phone
203-785-4651
Email
vince.faustino@yale.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Tara McPartland, MSW, MPH
Phone
203-737-7173
Email
tara.mcpartland@yale.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
E. Vincent Faustino, MD, MHS
Organizational Affiliation
Associate Professor of Pediatrics, Yale School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's of Alabama
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Meghan Murdock, RN
Email
Mmdmurdock@uabmc.edu
First Name & Middle Initial & Last Name & Degree
Michele Kong, MD
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yamila Sierra
Email
Yamila.Sierra@childrenscolorado.org
First Name & Middle Initial & Last Name & Degree
Matt Leroue, MD
Facility Name
Yale-New Haven Children's Hospital
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
E. Vincent Faustino, MD, MHS
First Name & Middle Initial & Last Name & Degree
Vincent Faustino
Facility Name
Johns Hopkins All Children's
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lexi Dallas
Email
adallas2@jhmi.edu
First Name & Middle Initial & Last Name & Degree
Anthony Sochet, MD
Facility Name
Stead Family Children's Hospital
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maureen Austin, RN, MPH, BSN
Email
Maureen-Austin@uiowa.edu
First Name & Middle Initial & Last Name & Degree
Madhuradhar Chegondi, MBBS, MD
Facility Name
Children's Hospital St. Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pamela Stone, RN
Email
stone.p@wustl.edu
First Name & Middle Initial & Last Name & Degree
Amanda Kolmar, MD
Facility Name
Hassenfeld Children's Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sandra Deygoo
Email
nagamah.deygoo@nyulangone.org
First Name & Middle Initial & Last Name & Degree
Michelle Ramirez, MD
Facility Name
New York Presbyterian Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marianne Nellis, MD
Email
man9026@med.cornell.edu
First Name & Middle Initial & Last Name & Degree
Liliko Chung
Email
lhc4027@med.cornell.edu
First Name & Middle Initial & Last Name & Degree
Marianne Nellis, MD
Facility Name
Golisano Children's Hospital
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eileen Taillie
Email
Eileen_Taillie@URMC.Rochester.edu
First Name & Middle Initial & Last Name & Degree
Jill Cholette, MD
Facility Name
Maria Fareri Children's Hospital
City
Valhalla
State/Province
New York
ZIP/Postal Code
10595
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
William Cuddy
Email
William.Cuddy@wmchealth.org
First Name & Middle Initial & Last Name & Degree
Matthew Pinto, MD
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lisa Steele Steele, RN
Email
Lisa.Steele@NationwideChildrens.org
First Name & Middle Initial & Last Name & Degree
Jennifer Muszynski, MD
Facility Name
University of Oklahoma
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tracy Jones
Email
Tracy-Jones@ouhsc.edu
First Name & Middle Initial & Last Name & Degree
Teddy Muisyo, MD
Facility Name
Penn State Hershey Children's Hospital
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Debbie Spear, RN
Email
dspear@pennstatehealth.psu.edu
First Name & Middle Initial & Last Name & Degree
Elizabeth Kerris, MD
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
MD
First Name & Middle Initial & Last Name & Degree
Christine Glau, MD
Facility Name
Children's Hospital of Richmond
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23219
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Megan Scott, CCRC
Email
Megan.Scott@vcuhealth.org
First Name & Middle Initial & Last Name & Degree
Vu Nguyen, MD
Facility Name
Children's Hospital Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sadaf Shad, MD
Email
sshad@mcw.edu
First Name & Middle Initial & Last Name & Degree
Hilary Schreiber, MD

12. IPD Sharing Statement

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Catheter-Related Early Thromboprophylaxis With Enoxaparin Studies

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