Clinical trial NCT04924322: Catheter-Related Early Thromboprophylaxis With Enoxaparin Studies
Official title: Age-dependent Heterogeneity in the Efficacy of Prophylaxis With Enoxaparin Against Catheter-associated Thrombosis in Critically Ill Children
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Deep Venous Thrombosis
Keywords: child
critical illness
venous thromboembolism
enoxaparin
thrombin generation
bleed
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: Children's Hospital Colorado
name: Children's Hospital of Philadelphia
name: BJC HealthCare
name: Medical College of Wisconsin
name: Children's of Alabama
name: Golisano Children's Hospital
name: Maria Fareri Children's Hospital
name: Nationwide Children's Hospital
name: New York Presbyterian Hospital
name: Penn State University
name: University of Iowa
name: Johns Hopkins All Children's Hospital
name: University of Oklahoma
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Children's Hospital of Illinois OSF Saint Francis Medical Center
name: Hassenfeld Children's Hospital
First posted: 2021-06-11
Enrollment: 258
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of children with CADVT
timeFrame: Up to removal of CVC (maximum of 28 days)
Secondary outcomes:
measure: Number of children with any VTE
timeFrame: Up to removal of CVC (maximum of 28 days)
measure: Number of children with clinically apparent CADVT
timeFrame: Up to removal of CVC (maximum of 28 days)
measure: Number of children with clinically apparent VTE
timeFrame: Up to removal of CVC (maximum of 28 days)
measure: Number of children with clinically relevant bleeding
timeFrame: Maximum of 36 hours after the last dose of enoxaparin
measure: Number of children with any bleeding
timeFrame: Maximum of 36 hours after the last dose of enoxaparin
measure: Number of children with heparin-induced thrombocytopenia
timeFrame: Maximum of 36 hours after the last dose of enoxaparin
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's of Alabama
state: Alabama
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale-New Haven Children's Hospital
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida -UF Health
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's
state: Florida
city: Peoria
country: United States
facility: Children's Hospital of Illinois at OSF Saint Francis Medical Center
state: Illinois
city: Iowa City
country: United States
facility: Stead Family Children's Hospital
state: Iowa
city: Saint Louis
country: United States
facility: Children's Hospital St. Louis
state: Missouri
city: New York
country: United States
facility: Hassenfeld Children's Hospital
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital
state: New York
city: Rochester
country: United States
facility: Golisano Children's Hospital
state: New York
city: Valhalla
country: United States
facility: Maria Fareri Children's Hospital
state: New York
city: Cleveland
country: United States
facility: UH Rainbow Babies & Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
city: Hershey
country: United States
facility: Penn State Hershey Children's Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Austin
country: United States
facility: Dell Children's Medical Canter
state: Texas
city: Dallas
country: United States
facility: UTSW Medical Center; Children's Medical Center of Dallas
state: Texas
city: Richmond
country: United States
facility: Children's Hospital of Richmond
state: Virginia
city: Milwaukee
country: United States
facility: Children's Hospital Wisconsin
state: Wisconsin
Study officials:
affiliation: Associate Professor of Pediatrics, Yale School of Medicine
name: E. Vincent Faustino, MD, MHS
role: PRINCIPAL_INVESTIGATOR
References: