Catheter-Related Early Thromboprophylaxis With Enoxaparin (CRETE) Trial (CRETE)

Prevention of Central Venous Catheter-associated Thrombosis in Critically Ill Children: A Multicenter Phase 2b Trial

The purpose of this phase 2a, multi-center, randomized controlled study, is to explore the efficacy of early prophylaxis against catheter-associated deep venous thrombosis (CADVT) in critically ill children.

Study Overview

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

Detailed Description

Critical illness and the presence of a central venous catheter (CVC) are the most important risk factors for deep venous thrombosis (DVT) in children. Catheter-associated thrombosis (CADVT) is highly prevalent and associated with poor outcomes in critically ill children. Yet, based on underpowered pediatric trials, prophylaxis against CADVT is not recommended in children. The recommendation to provide prophylaxis against thrombosis in critically ill adults should not be applied to children because the hemostatic system and co-morbidities vastly differ between age groups. Pivotal trials are urgently needed to determine whether prophylaxis can prevent CADVT and its complications in critically ill children. However, the timing and extent of reduction in thrombin generation, the biochemical goal of prophylaxis, needed to prevent CADVT in children are unclear. The goal of this application is to explore the efficacy of early prophylaxis against CADVT in critically ill children. Aim 1 is to obtain preliminary evidence on the effect of early prophylaxis on the incidence of CADVT in critically ill children. Based on the natural history of CADVT, we hypothesize that among critically ill children, prophylaxis administered <24 hours after catheter insertion decreases the incidence of ultrasound-diagnosed CADVT compared with no prophylaxis. In this phase 2a trial, children admitted to the intensive care unit with a newly inserted central venous catheter will receive enoxaparin adjusted according to anti-Xa activity, a control group will not receive enoxaparin adjusted according to anti-Xa activity. Enoxaparin has become the "standard" pediatric anticoagulant for prophylaxis despite the absence of conclusive data. We will use Bayesian approach to determine whether further trials are warranted. Aim 2 is to evaluate the effect of an anti-Xa activity-directed prophylactic strategy on thrombin generation in critically ill children. We hypothesize that among critically ill children, standard prophylactic dose of enoxaparin adjusted by anti-Xa activity reduces thrombin generation to <700 nanomolar-minute (nM.min), as measured by endogenous thrombin potential (ETP). In non-critically ill adults, prophylactic dose of enoxaparin proven to prevent DVT reduces ETP to <700 nM.min. Endogenous thrombin potential is the best available measure of thrombin generation. We will measure endogenous thrombin potential and anti-Xa activity at multiple time points then examine their relationship in all children enrolled in the phase 2a trial. The proposed research challenges the current paradigm on prophylaxis against CADVT in children. High quality evidence is needed to prevent CADVT and its complications in this vulnerable population.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University Yale New Haven Health
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis Children's Hospital-Washington University School of Medicine-
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medicine
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center-Golisano Children's Hospital-
    • Valhalla, New York, United States, 10595
      • Maria Fareri Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin/Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria

1. Untunneled CVC inserted in the internal jugular or femoral vein within the past 24 hours
2. Child anticipated to stay in the pediatric intensive care unit ≥48 hours
3. CVC anticipated to be required for ≥24 hours
4. >36 weeks corrected gestational age to <18 years old

Exclusion Criteria

1. Coagulopathy (i.e., international normalized ratio >2.0, activated partial thromboplastin time >50 seconds or platelet count <50,000/mm3)
2. Known bleeding disorder
3. Clinically relevant bleeding as defined by the International Society on Thrombosis and Hemostasis (i.e., Hb decreased ≥2 g/dl in 24 hours, required medical or surgical intervention to restore hemostasis, or in a critical organ system [i.e., retroperitoneum, pulmonary, intracranial or central nervous system])
4. <60 days from a clinically relevant bleeding as defined above
5. <7 days after trauma or surgery
6. Anticipated surgery within 48 hours after insertion of the CVC
7. Renal failure (i.e., creatinine clearance <30 mL/min)
8. Presence of epidural catheter
9. Currently taking an antithrombotic agent (e.g., low molecular weight heparin (LMWH), unfractionated heparin (UFH) at therapeutic doses, Coumadin or aspirin)
10. Radiologically documented DVT at the site of insertion of the CVC in the previous 6 weeks
11. Known hypersensitivity to heparin or its components, including pork products
12. History of heparin-induced thrombocytopenia (HIT) (i.e., positive serotonin release assay)
13. Currently pregnant
14. Currently lactating
15. Prior enrollment in the study
16. Limitation of care

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Prophylaxis with enoxaparin; A clinical nurse will administer enoxaparin subcutaneously <24 hours after insertion of the central venous catheter and then give enoxaparin subcutaneously every 12 hours until the removal of the catheter.	Drug: Enoxaparin; The clinical nurse will give enoxaparin subcutaneously every 12 hours at the currently used starting dose of 0.75 mg/kg for children ≤2 months old or 0.5 mg/kg (maximum of 40 mg) for older children. The 1st dose will be given <24 hours after insertion of the catheter. Doses will be adjusted to target an anti-Xa level of 0.2-0.5 IU/mL.; Other Names: Lovenox
NO_INTERVENTION: Control arm; Participants randomized to the control arm will receive no 'placebo' intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Central Venous Catheter (CVC)- Associated Deep Vein Thrombosis (DVT)	Thrombus in the central vein where the CVC was inserted that is clinically suspected then confirmed radiologically, an incidental radiologic finding, or diagnosed with the study-related active surveillance ultrasound	Up to removal of CVC, an average of 6 days
Endogenous Thrombin Potential	An established measure of coagulation status and is the best method to measure thrombin generation. It directly measures the amount of thrombin generation over time capturing the effects of natural (i.e., subject's coagulation status) and pharmacological (e.g., enoxaparin) pro- and anticoagulants. Endogenous thrombin potential is measured using thrombin generation assay.	Day of, day after and day 4 after insertion of the CVC

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number With Other Thromboembolic Events	Thrombus in the deep vein of any extremity or PE that is clinically suspected then confirmed radiologically, an incidental radiologic finding, excluding DVT diagnosed with the study-related active surveillance ultrasound	Up to removal of CVC, an average of 6 days
Length of Stay in the Pediatric Intensive Care Unit in Days	Duration of stay in the pediatric intensive care unit from the day of enrollment	Up to day of discharge from the pediatric intensive care unit, an average of 10 days
Length of Stay in the Hospital	Duration of stay in the hospital from the day of enrollment	Up to day of discharge from the hospital, an average of 18 days
Number With Clinically Relevant Bleeding	Bleeding that is fatal, associated with a decrease in hemoglobin by ≥2 g/dl in 24 hours, requires medical or surgical intervention to restore hemostasis, or is in the retroperitoneum, pulmonary, intracranial or central nervous system as defined by International Society of Thrombosis and Haemostasis	Up to 30 hours after the last enoxaparin dose
Number With Laboratory Confirmed Heparin-induced Thrombocytopenia	Heparin-induced thrombocytopenia that is diagnosed with a positive serotonin release assay	Up to removal of CVC, an average of 6 days
Number of Mortality	In-hospital mortality during the subject's admission	Up to day of discharge from the hospital, average of 18 days
Number of Enrolled Eligible Children	Number of eligible children enrolled in the study.	Up to 24 hours after insertion of CVC
Time to 1st Dose of Enoxaparin	Time to first dose of enoxaparin	Up to 48 hours after insertion of CVC
Time to Target Anti-Xa Activity	Time from insertion of the CVC to time that anti-Xa activity was within 0.2-0.5 IU/mL.	Up to removal of CVC, an average of 6 days
Number of Missed Doses of Enoxaparin	Number of doses of enoxaparin that were not administered. This outcome measure was only applicable to the enoxaparin arm.	Up to removal of CVC, an average of 6 days
Number of Children With Ultrasound	Number of children in whom ultrasound was not performed.	Up to 24 hours after removal of CVC

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Weill Medical College of Cornell University; Children's Hospital and Health System Foundation, Wisconsin; St. Louis Children's Hospital; Dell Children's Medical Center of Central Texas; Maria Fareri Children's Hospital; University of Rochester Golisano Children's Hospital
• Investigators: Principal Investigator: E. Vincent S Faustino, MD, MHS, Associate Professor of Pediatrics, Yale School of Medicine

Publications and helpful links

General Publications

• Faustino EVS, Raffini LJ, Hanson SJ, Cholette JM, Pinto MG, Li S, Kandil SB, Nellis ME, Shabanova V, Silva CT, Tala JA, McPartland T, Spinella PC; CRETE Trial Investigators and the Pediatric Critical Care Blood Research Network (BloodNet) of the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI); CRETE Trial Investigators: Clinical Coordinating Center:; and; Data Coordinating Center:; and; Outcomes Adjudication Committee:; and; Data and Safety Monitoring Board:; and; Independent Safety Monitor:; and; Children's Hospital Wisconsin:; and; Dell Children's Medical Center:; and; Maria Fareri Children's Hospital:; and; St. Louis Children's Hospital:; and; University of Rochester Golisano Children's Hospital:; and; Weill Cornell Medical Center:; and; Yale-New Haven Children's Hospital:; and; CRETE Trial Investigators and the Pediatric Critical Care Blood Research Network (BloodNet) of the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI) and CRETE Trial Investigators: Clinical Coordinating Center: and and and Data Coordinating Center: and and and Outcomes Adjudication Committee: and and and Data and Safety Monitoring Board: and and and Independent Safety Monitor: and and and Children's Hospital Wisconsin: and and and Dell Children's Medical Center: and and and Maria Fareri Children's Hospital: and and and St. Louis Children's Hospital: and and and University of Rochester Golisano Children's Hospital: and and and Weill Cornell Medical Center: and and and and Yale-New Haven Children's Hospital: and and. Age-Dependent Heterogeneity in the Efficacy of Prophylaxis With Enoxaparin Against Catheter-Associated Thrombosis in Critically Ill Children: A Post Hoc Analysis of a Bayesian Phase 2b Randomized Clinical Trial. Crit Care Med. 2021 Apr 1;49(4):e369-e380. doi: 10.1097/CCM.0000000000004848.
• Faustino EVS, Shabanova V, Raffini LJ, Kandil SB, Li S, Pinto MG, Cholette JM, Hanson SJ, Nellis ME, Silva CT, Chima R, Sharathkumar A, Thomas KA, McPartland T, Tala JA, Spinella PC; CRETE Trial Investigators and the Pediatric Critical Care Blood Research Network (BloodNet) of the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI). Efficacy of Early Prophylaxis Against Catheter-Associated Thrombosis in Critically Ill Children: A Bayesian Phase 2b Randomized Clinical Trial. Crit Care Med. 2021 Mar 1;49(3):e235-e246. doi: 10.1097/CCM.0000000000004784.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 5, 2017
• Primary Completion (ACTUAL): August 16, 2019
• Study Completion (ACTUAL): August 16, 2019

Study Registration Dates

• First Submitted: December 19, 2016
• First Submitted That Met QC Criteria: December 21, 2016
• First Posted (ESTIMATE): December 28, 2016

Study Record Updates

• Last Update Posted (ACTUAL): July 13, 2020
• Last Update Submitted That Met QC Criteria: July 10, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: child; venous thromboembolism; critical illness; enoxaparin; thrombin generation
• 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: 1302011506; 1R21HD089131-01A1 (NIH)

Drug and device information, study documents

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