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

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ClinicalTrials.gov Identifier: NCT03003390
Recruitment Status : Terminated (Met protocol defined stopping rule for futility)
First Posted : December 28, 2016
Last Update Posted : March 9, 2020
Sponsor:
Collaborators:
St. Louis Children's Hospital
Dell Children’s Medical Center of Central Texas
Children's Hospital and Health System Foundation, Wisconsin
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Yale University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Deep Venous Thrombosis Drug: Enoxaparin Phase 2

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 nM.min, as measured by 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Eligible subjects will be randomized 1:1 to treatment or control.
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Prevention of Central Venous Catheter-associated Thrombosis in Critically Ill Children: A Multicenter Phase 2b Trial
Actual Study Start Date : April 5, 2017
Actual Primary Completion Date : August 16, 2019
Actual Study Completion Date : August 16, 2019

Resource links provided by the National Library of Medicine


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 Name: Lovenox

No Intervention: Control arm
Participants randomized to the control arm will receive no 'placebo' intervention.



Primary Outcome Measures :
  1. Presence of CADVT [ Time Frame: Up to removal of CVC, an average of 6 days ]
  2. Endogenous thrombin potential [ Time Frame: Specific time points from prior to administration of enoxaparin to removal of CVC, an average of 6 days ]

Secondary Outcome Measures :
  1. Presence other thromboembolic events [ Time Frame: Up to removal of CVC, an average of 6 days ]
  2. Length of stay in the pediatric intensive care unit [ Time Frame: Up to day of discharge from the pediatric intensive care unit, an average of 10 days ]
  3. Length of stay in the hospital [ Time Frame: Up to day of discharge from the hospital, an average of 18 days ]
  4. Presence of clinically relevant bleeding [ Time Frame: Up to 30 hours after the last enoxaparin dose ]
  5. Presence of laboratory confirmed heparin-induced thrombocytopenia [ Time Frame: Up to removal of CVC, an average of 6 days ]
  6. Mortality [ Time Frame: Up to day of discharge from the hospital, average of 18 days ]
  7. Proportion of enrolled eligible children [ Time Frame: Up to 24 hours after insertion of CVC ]
  8. Time to 1st dose of enoxaparin [ Time Frame: Up to 48 hours after insertion of CVC ]
  9. Time to target anti-Xa activity [ Time Frame: Up to removal of CVC, an average of 6 days ]
  10. Proportion of missed doses of enoxaparin [ Time Frame: Up to removal of CVC, an average of 6 days ]
  11. Proportion of children with ultrasound [ Time Frame: Up to 24 hours after removal of CVC ]


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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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., LMWH, 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 HIT (i.e., positive serotonin release assay)
  13. Currently pregnant
  14. Currently lactating
  15. Prior enrollment in the study
  16. Limitation of care

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03003390


Locations
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United States, Connecticut
Yale University Yale New Haven Health
New Haven, Connecticut, United States, 06520
United States, Missouri
Saint Louis Children's Hospital-Washington University School of Medicine—
Saint Louis, Missouri, United States, 63110
United States, New York
Weill Cornell Medicine
New York, New York, United States, 10065
University of Rochester Medical Center-Golisano Children's Hospital-
Rochester, New York, United States, 14642
Maria Fareri Children's Hospital
Valhalla, New York, United States, 10595
United States, Wisconsin
Children's Hospital of Wisconsin/Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Yale University
St. Louis Children's Hospital
Dell Children’s Medical Center of Central Texas
Children's Hospital and Health System Foundation, Wisconsin
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: E. Vincent S Faustino, MD, MHS Associate Professor of Pediatrics, Yale School of Medicine

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Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT03003390    
Other Study ID Numbers: 1302011506
1R21HD089131-01A1 ( U.S. NIH Grant/Contract )
First Posted: December 28, 2016    Key Record Dates
Last Update Posted: March 9, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Yale University:
child
critical illness
venous thromboembolism
enoxaparin
thrombin generation
Additional relevant MeSH terms:
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Thrombosis
Venous Thrombosis
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases